Editing Benzodiazepine

{{Short description|Class of depressant drugs}}
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{{Infobox drug class
| Name                = Benzodiazepines
| Image               = Benzodiazepine.svg
| ImageClass          = skin-invert-image
| Width               = 
| Alt                 = <!-- See WP:ALT -->
| Caption             = Structural formula of benzodiazepines.
| Use                 = [[Anxiety disorder]]s, [[seizures]], [[muscle spasms]], [[panic disorder]]
| ATC_prefix          = N05BA 
| Mode_of_action      = [[GABAA receptor|GABA<sub>A</sub> receptor]]
| Mechanism_of_action = 
| Biological_target   = 
| Chemical_class      = 
<!-- Clinical data -->
| Drugs.com           = 
| Consumer_Reports    = 
| medicinenet         = benzodiazepines-oral
| rxlist              = 94661
<!-- External links -->
| MeshID              = D001569
}}
'''Benzodiazepines''' ('''BZD''', '''BDZ''', '''BZs'''), colloquially known as "'''benzos'''", are a class of [[central nervous system]] (CNS) [[depressant|depressant drugs]] whose core chemical structure is the fusion of a [[benzene]] ring and a [[diazepine]] ring. They are prescribed to treat conditions such as [[anxiety disorder]]s, [[insomnia]], and [[seizures]]. The first benzodiazepine, [[chlordiazepoxide]] (Librium), was discovered accidentally by [[Leo Sternbach]] in 1955, and was made available in 1960 by [[Roche|Hoffmann–La Roche]], which followed with the development of [[diazepam]] (Valium) three years later, in 1963.<ref name="isbn0-19-517668-5"/> By 1977, benzodiazepines were the most prescribed medications globally; the introduction of [[selective serotonin reuptake inhibitors]] (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.<ref>{{cite journal | vauthors = Balon R, Starcevic V, Silberman E, Cosci F, Dubovsky S, Fava GA, Nardi AE, Rickels K, Salzman C, Shader RI, Sonino N | title = The rise and fall and rise of benzodiazepines: a return of the stigmatized and repressed | journal = Revista Brasileira de Psiquiatria | volume = 42 | issue = 3 | pages = 243–244 | date = 9 March 2020 | pmid = 32159714 | pmc = 7236156 | doi = 10.1590/1516-4446-2019-0773 }}</ref><ref>{{cite book|title=Treating Alcohol and Drug Problems in Psychotherapy Practice Doing What Works|date=2011|publisher=Guilford Publications|location=New York|isbn=978-1-4625-0438-1|page=47|url=https://books.google.com/books?id=1hCHzJkZ8JIC&pg=PA47}}</ref>

<!-- Medical uses -->
Benzodiazepines are [[depressant]]s that enhance the effect of the [[neurotransmitter]] [[gamma-Aminobutyric acid|gamma-aminobutyric acid]] (GABA) at the [[GABAA receptor|GABA<sub>A</sub> receptor]], resulting in [[sedative]], [[hypnotic]] ([[Sleep induction|sleep-inducing]]), [[anxiolytic]] (anti-anxiety), [[anticonvulsant]], and [[muscle relaxant]] properties. High doses of many shorter-acting benzodiazepines may also cause [[anterograde amnesia]] and [[dissociation (psychology)|dissociation]].<ref name=ip2002/> These properties make benzodiazepines useful in treating [[anxiety]], [[panic disorder]], [[insomnia]], [[Psychomotor agitation|agitation]], [[epileptic seizure|seizures]], [[spasm|muscle spasms]], [[alcohol withdrawal]] and as a [[premedication]] for medical or dental procedures.<ref name=pmid18175099/> Benzodiazepines are categorized as short, intermediate, or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety.<ref name=sddat/>

<!-- Side effects -->
Benzodiazepines are generally viewed as safe and effective for short-term use of two to four weeks,<ref>{{cite journal | vauthors = Ashton H | title = The diagnosis and management of benzodiazepine dependence | journal = Current Opinion in Psychiatry | volume = 18 | issue = 3 | pages = 249–255 | date = May 2005 | pmid = 16639148 | doi = 10.1097/01.yco.0000165594.60434.84 | s2cid = 1709063 }}</ref> although [[cognitive impairment]] and [[paradoxical effect]]s such as aggression or behavioral [[disinhibition]] can occur.<ref name=pmid18922233/> According to the [[Government of Victoria]]'s (Australia) [[Department of Health (Victoria)|Department of Health]], long-term use can cause "impaired thinking or memory loss, anxiety and depression, irritability, paranoia, aggression, etc."<ref name="Better Health Channel 2000 i441">{{cite web | title=Benzodiazepines | website=Better Health Channel | date=19 May 2023 | url=https://www.betterhealth.vic.gov.au/health/healthyliving/benzodiazepines}}</ref> A minority of people have [[paradoxical reactions]] after taking benzodiazepines such as worsened agitation or panic.<ref name=pmid18922233/> Benzodiazepines are often prescribed for as-needed use, which is under-studied, but probably safe and effective to the extent that it involves intermittent short-term use.<ref>{{Cite journal |last=Krieger |first=Arthur |date=27 April 2025 |title=Benzos (as) needed: research into as-needed and intermittent benzodiazepines for anxiety is required for comprehensive best prescribing practices |journal=Frontiers in Psychiatry |volume=16|doi=10.3389/fpsyt.2025.1569416 |doi-access=free |pmid=40357517 |pmc=12066482 }}</ref>

Benzodiazepines are associated with an increased risk of [[suicide]] due to aggression, impulsivity, and negative withdrawal effects.<ref name="Dodds_2017">{{cite journal | vauthors = Dodds TJ | title = Prescribed Benzodiazepines and Suicide Risk: A Review of the Literature | journal = The Primary Care Companion for CNS Disorders | volume = 19 | issue = 2 | date = March 2017 | pmid = 28257172 | doi = 10.4088/PCC.16r02037 | doi-access = free | title-link = doi }}</ref> Long-term use is controversial because of concerns about [[drug tolerance|decreasing effectiveness]], [[physical dependence]], [[benzodiazepine withdrawal syndrome]], and an increased risk of [[dementia]] and [[cancer]].<ref name=pmid18671662/><ref name=pmid19062773/><ref name="pmid29926372"/><ref name="Use of benzodiazepine and risk of c">{{cite journal | vauthors = Kim HB, Myung SK, Park YC, Park B | title = Use of benzodiazepine and risk of cancer: A meta-analysis of observational studies | journal = International Journal of Cancer | volume = 140 | issue = 3 | pages = 513–525 | date = February 2017 | pmid = 27667780 | doi = 10.1002/ijc.30443 | s2cid = 25777653 | doi-access = free | title-link = doi }}</ref> The elderly are at an increased risk of both short- and [[long-term effects of benzodiazepines|long-term adverse effects]],<ref name=tdamobd2004/><ref name=ohop/> and as a result, all benzodiazepines are listed in the [[Beers Criteria|Beers List]] of inappropriate medications for older adults.<ref name=agsubc2015>{{cite journal | publisher = The American Geriatrics Society 2015 Beers Criteria Update Expert Panel | title = American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults | journal = Journal of the American Geriatrics Society | volume = 63 | issue = 11 | pages = 2227–2246 | date = November 2015 | pmid = 26446832 | doi = 10.1111/jgs.13702 | s2cid = 38797655 | vauthors = Fick DM, Semla TP, Beizer J, Brandt N, Dombrowski R, DuBeau CE, Eisenberg W, Epplin JJ, Flanagan N, Giovannetti E, Hanlon J | collaboration = American Geriatrics Society 2015 Beers Criteria Update Expert Panel }}</ref> There is controversy concerning the safety of benzodiazepines in pregnancy. While they are not major [[teratogens]], uncertainty remains as to whether they cause [[cleft palate]] in a small number of babies and whether neurobehavioural effects occur as a result of prenatal exposure;<ref name=ACOG /> they are known to cause [[Neonatal withdrawal|withdrawal symptoms in the newborn]].

In an overdose, benzodiazepines can cause dangerous [[coma|deep unconsciousness]], but are less toxic than their predecessors, the [[barbiturate]]s, and death rarely results when a benzodiazepine is the only drug taken. Combined with other [[central nervous system]] (CNS) [[depressant]]s such as [[alcohol (drug)|alcohol]] and [[opioid]]s, the potential for toxicity and fatal overdose increases significantly.<ref name=pmid9780123/><ref>{{cite press release |title=FDA requires strong warnings for opioid analgesics, prescription opioid cough products, and benzodiazepine labeling related to serious risks and death from combined use |url=https://www.fda.gov/news-events/press-announcements/fda-requires-strong-warnings-opioid-analgesics-prescription-opioid-cough-products-and-benzodiazepine |website=U.S. [[Food and Drug Administration]] (FDA) |access-date=1 September 2016|date=31 August 2016}}</ref> Benzodiazepines are commonly [[recreational drug use|used recreationally]] and also often taken [[poly drug use|in combination]] with other addictive substances, and are [[prohibition of drugs|controlled]] in most countries.<ref name=Charlson_2009/><ref name=pmid10707430/><ref name=pmid10622686/>
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==Medical uses==
{{See also|List of benzodiazepines}}
[[File:Midazolam.JPG|thumb|alt=Two 10 mL bottles labeled Midazolam. The bottle on the left has a label in red and says 1 mg/mL; the one on the right is in green and says 5 mg/mL. Both bottles have much fine print.|[[Midazolam]] 1 & 5 mg/mL [[Drug injection|injections]] (Canada)]]
Benzodiazepines possess [[psycholeptic]], [[sedative]], [[hypnotic]], [[anxiolytic]], anticonvulsant, [[muscle relaxant]], and [[anterograde amnesia|amnesic]] actions,<ref name=ip2002>{{cite book |vauthors=Page C, Michael C, Sutter M, Walker M, Hoffman BB |title=Integrated Pharmacology |edition=2nd |year=2002 |publisher=C.V. Mosby |isbn=978-0-7234-3221-0 }}</ref><ref name=pmid18175099>{{cite book | vauthors = Olkkola KT, Ahonen J | chapter = Midazolam and Other Benzodiazepines |editor1=Schüttler J |editor2=Schwilden H |title = Modern Anesthetics | series = Handbook of Experimental Pharmacology | volume = 182 | issue = 182 | pages = 335–360 | year = 2008 | pmid = 18175099 | doi = 10.1007/978-3-540-74806-9_16 | isbn = 978-3-540-72813-9 }}</ref> which are useful in a variety of indications such as [[alcohol dependence]], [[seizures]], [[anxiety disorders]], [[panic]], [[psychomotor agitation|agitation]], and insomnia. Most are administered orally; however, they can also be given [[intravenous therapy|intravenously]], [[intramuscular injection|intramuscularly]], or [[Rectal administration|rectally]].<ref name="BNF_2009">{{cite book |title=British National Formulary (BNF 57) |publisher=Royal Pharmaceutical Society of Great Britain |year=2009 |isbn=978-0-85369-845-6 |title-link=British National Formulary }}</ref>{{rp|189|date=November 2012}} In general, benzodiazepines are well tolerated and are safe and effective drugs in the short term for a wide range of conditions.<ref name=Perugi>{{cite journal | vauthors = Perugi G, Frare F, Toni C | title = Diagnosis and treatment of agoraphobia with panic disorder | journal = CNS Drugs | volume = 21 | issue = 9 | pages = 741–764 | year = 2007 | pmid = 17696574 | doi = 10.2165/00023210-200721090-00004 | s2cid = 43437233 }}</ref><ref name=Tesar>{{cite journal | vauthors = Tesar GE | title = High-potency benzodiazepines for short-term management of panic disorder: the U.S. experience | journal = The Journal of Clinical Psychiatry | volume = 51 | issue = Suppl | pages = 4–10; discussion 50–53 | date = May 1990 | pmid = 1970816 }}</ref> Tolerance can develop to their effects and there is also a risk of [[drug dependence|dependence]], and upon discontinuation a withdrawal syndrome may occur. These factors, combined with other possible secondary effects after prolonged use such as psychomotor, cognitive, or memory impairments, limit their long-term applicability.<ref>{{cite journal | vauthors = Faught E | title = Treatment of refractory primary generalized epilepsy | journal = Reviews in Neurological Diseases | volume = 1 | issue = Suppl 1 | pages = S34–43 | year = 2004 | pmid = 16400293 }}</ref><ref>{{cite journal | vauthors = Allgulander C, Bandelow B, Hollander E, Montgomery SA, Nutt DJ, Okasha A, Pollack MH, Stein DJ, Swinson RP | title = WCA recommendations for the long-term treatment of generalized anxiety disorder | journal = CNS Spectrums | volume = 8 | issue = Suppl 1 | pages = 53–61 | date = August 2003 | pmid = 14767398 | doi = 10.1017/S1092852900006945 | s2cid = 32761147 }}</ref> [[Long-term effects of benzodiazepines|The effects of long-term use]] or misuse include the tendency to cause or worsen [[cognitive deficit]]s, depression, and anxiety.<ref name=tdamobd2004>{{cite journal | vauthors = Ashton H | title = The diagnosis and management of benzodiazepine dependence | journal = Current Opinion in Psychiatry | volume = 18 | issue = 3 | pages = 249–255 | date = May 2005 | pmid = 16639148 | doi = 10.1097/01.yco.0000165594.60434.84 | s2cid = 1709063 | url = https://www.benzo.org.uk/amisc/ashdiag.pdf }}</ref><ref name=ohop/> The [[College of Physicians and Surgeons of British Columbia]] recommends discontinuing the usage of benzodiazepines in those on opioids and those who have used them long term.<ref>{{cite web | url = https://www.cpsbc.ca/for-physicians/college-connector/2016-V04-01/07 | title = Benzodiazepines in chronic pain | date = February 2016 | access-date = 22 September 2016 | archive-date = 23 September 2016 | archive-url = https://web.archive.org/web/20160923185441/https://www.cpsbc.ca/for-physicians/college-connector/2016-V04-01/07 | url-status = dead }}</ref> Benzodiazepines can have serious adverse health outcomes, and these findings support clinical and regulatory efforts to reduce usage, especially in combination with non-benzodiazepine receptor agonists.<ref name=":0" />

===Panic disorder===
{{Further|Panic disorder}}
[[File:Lorazepam Orion.jpg|thumb|A box of Lorazepam Orion (Lorazepam) tablets]]

Benzodiazepines are usually administered orally; however, very occasionally [[lorazepam]] or [[diazepam]] may be given intravenously for the treatment of [[panic attack]]s.<ref name="BNF_2009"/>

Because of their effectiveness, tolerability, and rapid onset of [[anxiolytic]] action, benzodiazepines are frequently used for the treatment of [[anxiety]] associated with [[panic disorder]].<ref name="pmid15762816">{{cite journal | vauthors = Stevens JC, Pollack MH | title = Benzodiazepines in clinical practice: consideration of their long-term use and alternative agents | journal = The Journal of Clinical Psychiatry | volume = 66 | issue = Suppl 2 | pages = 21–27 | year = 2005 | pmid = 15762816 | quote = The frequent use of benzodiazepines for the treatment of anxiety is likely a reflection of their effectiveness, rapid onset of anxiolytic effect, and tolerability. }}</ref> However, there is disagreement among expert bodies regarding the long-term use of benzodiazepines for panic disorder. The views range from those holding benzodiazepines are not effective long-term<ref name=cgftmamoa2004/> and should be reserved for treatment-resistant cases<ref>{{cite journal | vauthors = Bandelow B, Zohar J, Hollander E, Kasper S, Möller HJ | title = World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Posttraumatic Stress Disorders | journal = The World Journal of Biological Psychiatry | volume = 3 | issue = 4 | pages = 171–199 | date = October 2002 | pmid = 12516310 | doi = 10.3109/15622970209150621 | s2cid = 922780 | doi-access = free | title-link = doi }}</ref> to those holding they are as effective in the long term as [[selective serotonin reuptake inhibitors]] (SSRIs).<ref name=APA/>

[[American Psychiatric Association]] (APA) guidelines, published in January 2009,<ref name="APA">{{cite web |url=http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=PanicDisorder_2e_PracticeGuideline |format = PDF |title= APA Practice Guideline for the Treatment of Patients With Panic Disorder, Second Edition |publisher=Work Group on Panic Disorder |date=January 2009 |access-date=12 July 2009 }}</ref> note that, in general, benzodiazepines are well tolerated, and their use for the initial treatment for panic disorder is strongly supported by numerous controlled trials. APA states that there is insufficient evidence to recommend any of the established panic disorder treatments over another. The choice of treatment between benzodiazepines, SSRIs, [[serotonin–norepinephrine reuptake inhibitors]] (SNRIs), [[tricyclic antidepressant]]s, and psychotherapy should be based on the patient's history, preference, and other individual characteristics. Selective serotonin reuptake inhibitors are likely to be the best choice of pharmacotherapy for many patients with panic disorder, but benzodiazepines are also often used, and some studies suggest that these medications are still used with greater frequency than the SSRIs. One advantage of benzodiazepines is that they alleviate the anxiety symptoms much more quickly than antidepressants, and therefore may be preferred in patients for whom rapid symptom control is critical. However, this advantage is offset by the possibility of developing [[benzodiazepine dependence]]. APA does not recommend benzodiazepines for persons with depressive symptoms or a recent history of [[substance use disorder]]. APA guidelines state that, in general, pharmacotherapy of panic disorder should be continued for at least a year, and that clinical experience supports continuing benzodiazepine treatment to prevent recurrence. Although major concerns about benzodiazepine tolerance and withdrawal have been raised, there is no evidence for significant dose escalation in patients using benzodiazepines long-term. For many such patients, stable doses of benzodiazepines retain their efficacy over several years.<ref name=APA/>

Guidelines issued by the UK-based [[National Institute for Health and Clinical Excellence]] (NICE), carried out a systematic review using different methodology and came to a different conclusion. They questioned the accuracy of studies that were not placebo-controlled. And, based on the findings of [[placebo-controlled studies]], they do not recommend use of benzodiazepines beyond two to four weeks, as tolerance and [[physical dependence]] develop rapidly, with withdrawal symptoms including [[rebound anxiety]] occurring after six weeks or more of use.<ref name=cgftmamoa2004>{{cite web |vauthors=McIntosh A, Cohen A, Turnbull N, Esmonde L, Dennis P, Eatock J, Feetam C, Hague J, Hughes I, Kelly J, Kosky N |title=Clinical guidelines and evidence review for panic disorder and generalised anxiety disorder |url=http://www.nice.org.uk/nicemedia/pdf/cg022fullguideline.pdf |publisher=National Collaborating Centre for Primary Care |year=2004 |access-date=16 June 2009 |archive-date=19 February 2009 |archive-url=https://web.archive.org/web/20090219140855/http://www.nice.org.uk/nicemedia/pdf/cg022fullguideline.pdf |url-status=dead }}</ref><ref>{{cite web |vauthors=Barbui C, Cipriani A |title=Proposal for the inclusion in the WHO Model List of Essential Medicines of a selective serotonin-reuptake inhibitor for Generalised Anxiety Disorder |url=http://who.int/selection_medicines/committees/expert/17/application/Section24_GAD.pdf |publisher=WHO Collaborating Centre for Research and Training in Mental Health |year=2009 |access-date=23 June 2009 |archive-date=5 May 2012 |archive-url=https://web.archive.org/web/20120505191411/http://who.int/selection_medicines/committees/expert/17/application/Section24_GAD.pdf |url-status=dead }}</ref> Nevertheless, benzodiazepines are still prescribed for long-term treatment of [[anxiety disorders]], although specific [[antidepressants]] and psychological therapies are recommended as the [[first-line treatment]] options with the [[anticonvulsant]] drug [[pregabalin]] indicated as a second- or third-line treatment and suitable for long-term use.<ref>{{cite journal | vauthors = Cloos JM, Ferreira V | title = Current use of benzodiazepines in anxiety disorders | journal = Current Opinion in Psychiatry | volume = 22 | issue = 1 | pages = 90–95 | date = January 2009 | pmid = 19122540 | doi = 10.1097/YCO.0b013e32831a473d | s2cid = 20715355 }}</ref> NICE stated that long-term use of benzodiazepines for panic disorder with or without [[agoraphobia]] is an unlicensed indication, does not have long-term efficacy, and is, therefore, not recommended by clinical guidelines. Psychological therapies such as [[cognitive behavioural therapy]] are recommended as a first-line therapy for panic disorder; benzodiazepine use has been found to interfere with therapeutic gains from these therapies.<ref name=cgftmamoa2004 />

===Generalized anxiety disorder===
{{Further|Generalized anxiety disorder}}
[[File:Boites d'alprazolam444.jpg|thumb|Alprazolam pills in boxes, as sold in [[France]]; both the original [[Pfizer]] brand product Xanax and various [[Generic drug|generic forms]] of alprazolam are depicted here.]]

Benzodiazepines have robust efficacy in the short-term management of [[generalized anxiety disorder]] (GAD) when standardized measures of anxiety are used as the outcome variable,<ref>{{cite journal | vauthors = Stimpfl JN, Mills JA, Strawn JR | title = Pharmacologic predictors of benzodiazepine response trajectory in anxiety disorders: a Bayesian hierarchical modeling meta-analysis | journal = CNS Spectrums | volume = 28 | issue = 1 | pages = 53–60 | date = February 2023 | pmid = 34593077 | pmc = 8971141 | doi = 10.1017/S1092852921000870 }}</ref> but did not demonstrate a favorable dropout rate compared to placebo in one meta-analysis.<ref name="pmid17881433">{{cite journal | vauthors = Martin JL, Sainz-Pardo M, Furukawa TA, Martín-Sánchez E, Seoane T, Galán C | title = Benzodiazepines in generalized anxiety disorder: heterogeneity of outcomes based on a systematic review and meta-analysis of clinical trials | journal = Journal of Psychopharmacology | volume = 21 | issue = 7 | pages = 774–782 | date = September 2007 | pmid = 17881433 | doi = 10.1177/0269881107077355 | s2cid = 1879448 }}</ref> A newer meta-analysis showed that benzodiazepines are significantly more effective than serotonergic agents, regardless of treatment length.<ref name="pmid29806492">{{cite journal | vauthors = Gomez AF, Barthel AL, Hofmann SG | title = Comparing the efficacy of benzodiazepines and serotonergic anti-depressants for adults with generalized anxiety disorder: a meta-analytic review | journal = Expert Opinion on Pharmacotherapy | volume = 19 | issue = 8 | pages = 883–894 | date = June 2018 | pmid = 29806492 | pmc = 6097846 | doi = 10.1080/14656566.2018.1472767 }}</ref> More research is needed, but unfortunately, newer randomized controlled trials are scarce for the off patent benzodiazepines. According to [[National Institute for Health and Clinical Excellence]] (NICE), benzodiazepines can be used in the immediate management of GAD, if necessary. However, they should not usually be given for longer than 2–4 weeks. The only medications NICE recommends for the longer term management of GAD are antidepressants.<ref name=NICECG022>{{cite web |title=Clinical Guideline 22 (amended). Anxiety: management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care |pages=23–25 |url=http://www.nice.org.uk/nicemedia/pdf/CG022NICEguidelineamended.pdf |publisher=National Institute for Health and Clinical Excellence |year=2007 |access-date=8 August 2009 |archive-url=https://web.archive.org/web/20120514111817/http://www.nice.org.uk/nicemedia/pdf/CG022NICEguidelineamended.pdf |archive-date=14 May 2012 |url-status=dead }}</ref>

Likewise, Canadian Psychiatric Association (CPA) recommends benzodiazepines [[alprazolam]], [[bromazepam]], lorazepam, and diazepam only as a second-line choice, if the treatment with two different antidepressants was unsuccessful.<ref name="pmid16933543">{{cite journal |author=Canadian Psychiatric Association |date=July 2006 |title=Clinical practice guidelines. Management of anxiety disorders |url=http://publications.cpa-apc.org/media.php?mid=440 |url-status=dead |journal=The Canadian Journal of Psychiatry |type=PDF |volume=51 |issue=8 Suppl 2 |pages=9S–91S |pmid=16933543 |archive-url=https://web.archive.org/web/20100714202950/http://publications.cpa-apc.org/media.php?mid=440 |archive-date=14 July 2010 |access-date=8 August 2009}}</ref> Although they are second-line agents, benzodiazepines can be used for a limited time to relieve severe anxiety and agitation. CPA guidelines state that after 4–6 weeks the effect of benzodiazepines may decrease to the level of placebo,<ref name="pmid16933543" /> and that benzodiazepines are less effective than antidepressants in alleviating [[rumination (psychology)|ruminative worry]], the core symptom of GAD, but that in some cases, a prolonged treatment with benzodiazepines as the add-on to an antidepressant may be justified. Evidence from reviews of benzodiazepine tolerance mechanisms<ref name=":2" /> and clonazepam use in psychiatric disorders<ref name="pmid16528135" /> is strongly discordant with the claim that benzodiazepines lose anxiolytic efficacy over a period of weeks, as these reviews present RCT evidence of continued anxiolytic efficacy at up to 22 weeks<ref name=":3" /> and observational (open-label) evidence of continued efficacy at up to 3 years.<ref name=":4" />

A 2015 review found a larger effect with medications than talk therapy.<ref name=Band2015>{{cite journal | vauthors = Bandelow B, Reitt M, Röver C, Michaelis S, Görlich Y, Wedekind D | title = Efficacy of treatments for anxiety disorders: a meta-analysis | journal = International Clinical Psychopharmacology | volume = 30 | issue = 4 | pages = 183–192 | date = July 2015 | pmid = 25932596 | doi = 10.1097/YIC.0000000000000078 | s2cid = 24088074 }}</ref> Medications with benefit include [[serotonin-noradrenaline reuptake inhibitors]], benzodiazepines, and [[selective serotonin reuptake inhibitors]].<ref name=Band2015/>

===Insomnia===
{{Further|Insomnia}}
[[File:Normison.jpg|thumb|[[Temazepam]] (Normison) 10 mg tablets]]
Benzodiazepines can be useful for short-term treatment of [[insomnia]]. Their use beyond 2 to 4 weeks is not recommended due to the risk of dependence. The Committee on Safety of Medicines report recommended that where long-term use of benzodiazepines for insomnia is indicated then treatment should be intermittent wherever possible.<ref>{{cite web|url= http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con2024428.pdf|archive-url= http://webarchive.nationalarchives.gov.uk/20141206140040/http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con2024428.pdf|url-status= dead|archive-date= 6 December 2014|title= Current problems|date= 1988|website= www.mhra.gov.uk|access-date= 21 March 2020}}</ref> It is preferred that benzodiazepines be taken intermittently and at the lowest effective dose. They improve sleep-related problems by shortening the time spent in bed before falling asleep, prolonging the sleep time, and, in general, reducing wakefulness.<ref name="nice-hypnotics">{{cite web|title=Technology Appraisal Guidance 77. Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia |url=http://www.nice.org.uk/nicemedia/pdf/TA077fullguidance.pdf |publisher=National Institute for Clinical Excellence |date=April 2004 |access-date=26 July 2009 |url-status=dead |archive-url=https://web.archive.org/web/20081203063917/http://www.nice.org.uk/nicemedia/pdf/TA077fullguidance.pdf |archive-date=3 December 2008 }}</ref><ref name="pmid17853625">{{cite journal | vauthors = Ramakrishnan K, Scheid DC | title = Treatment options for insomnia | journal = American Family Physician | volume = 76 | issue = 4 | pages = 517–526 | date = August 2007 | pmid = 17853625 | url = http://www.aafp.org/afp/2007/0815/p517.html }}</ref> However, they worsen sleep quality by increasing light sleep and decreasing deep sleep. Other drawbacks of hypnotics, including benzodiazepines, are possible tolerance to their effects, [[rebound insomnia]], and reduced slow-wave sleep and a withdrawal period typified by rebound insomnia and a prolonged period of anxiety and agitation.<ref name="handbook_of_integrative">{{cite book | vauthors = Carlstedt RA | title = Handbook of Integrative Clinical Psychology, Psychiatry, and Behavioral Medicine: Perspectives, Practices, and Research | date = 13 December 2009 | publisher = Springer Publishing Company | url = https://books.google.com/books?id=4Tkdm1vRFbUC | isbn = 978-0-8261-1094-7 | pages = 128–130 }}</ref><ref name="ahrq"/>

The list of benzodiazepines approved for the treatment of insomnia is fairly similar among most countries, but which benzodiazepines are officially designated as first-line hypnotics prescribed for the treatment of insomnia varies between countries.<ref name="pmid17853625"/> Longer-acting benzodiazepines such as [[nitrazepam]] and [[diazepam]] have residual effects that may persist into the next day and are, in general, not recommended.<ref name="nice-hypnotics"/>

Since the release of [[nonbenzodiazepines]], also known as z-drugs, in 1992 in response to safety concerns, individuals with insomnia and other sleep disorders have increasingly been prescribed nonbenzodiazepines (2.3% in 1993 to 13.7% of Americans in 2010), less often prescribed benzodiazepines (23.5% in 1993 to 10.8% in 2010).<ref name="Kaufmann_2016">{{cite journal | vauthors = Kaufmann CN, Spira AP, Alexander GC, Rutkow L, Mojtabai R | title = Trends in prescribing of sedative-hypnotic medications in the USA: 1993–2010 | journal = Pharmacoepidemiology and Drug Safety | volume = 25 | issue = 6 | pages = 637–645 | date = June 2016 | pmid = 26711081 | pmc = 4889508 | doi = 10.1002/pds.3951 }}</ref><ref>{{cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/019908_S000_AP&AE_LTRS&FPL.pdf |archive-url=https://ghostarchive.org/archive/20221009/http://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/019908_S000_AP&AE_LTRS&FPL.pdf |archive-date=9 October 2022 |url-status=live|title=Approval letter for Ambien|website=Food and Drug Administration}}</ref> It is not clear as to whether the new [[nonbenzodiazepine|non benzodiazepine]] hypnotics (Z-drugs) are better than the short-acting benzodiazepines. The efficacy of these two groups of medications is similar.<ref name="nice-hypnotics"/><ref name="ahrq"/> According to the US [[Agency for Healthcare Research and Quality]], indirect comparison indicates that side-effects from benzodiazepines may be about twice as frequent as from nonbenzodiazepines.<ref name="ahrq">{{cite web |vauthors=Buscemi N, Vandermeer B, Friesen C, Bialy L, Tubman M, Ospina M, Klassen TP, Witmans M |title=Manifestations and Management of Chronic Insomnia in Adults. Summary, Evidence Report/Technology Assessment: Number 125 | publisher = Agency for Healthcare Research and Quality |date=June 2005 |url=http://www.ahrq.gov/clinic/epcsums/insomnsum.pdf |archive-url=https://ghostarchive.org/archive/20221009/http://www.ahrq.gov/clinic/epcsums/insomnsum.pdf |archive-date=9 October 2022 |url-status=live }}</ref> Some experts suggest using nonbenzodiazepines preferentially as a first-line long-term treatment of insomnia.<ref name="pmid17853625"/> However, the UK [[National Institute for Health and Clinical Excellence]] did not find any convincing evidence in favor of Z-drugs. NICE review pointed out that short-acting Z-drugs were inappropriately compared in clinical trials with long-acting benzodiazepines. There have been no trials comparing short-acting Z-drugs with appropriate doses of short-acting benzodiazepines. Based on this, NICE recommended choosing the hypnotic based on cost and the patient's preference.<ref name="nice-hypnotics"/>

Older adults should not use benzodiazepines to treat insomnia unless other treatments have failed.<ref name="AGSfive"/> When benzodiazepines are used, patients, their caretakers, and their physician should discuss the increased risk of harms, including evidence that shows twice the incidence of [[traffic collisions]] among driving patients, and falls and hip fracture for older patients.<ref name="AGSfive">{{cite journal |author1 = American Geriatrics Society |author1-link = American Geriatrics Society |title = Five Things Physicians and Patients Should Question |journal = Choosing Wisely: An Initiative of the ABIM Foundation |url = http://www.choosingwisely.org/doctor-patient-lists/american-geriatrics-society/ |access-date = 1 August 2013 |archive-date = 1 September 2013 |archive-url = https://web.archive.org/web/20130901100140/http://www.choosingwisely.org/doctor-patient-lists/american-geriatrics-society/ |url-status = dead }}, which cites</ref><ref name="pmid16156679"/><ref>{{cite journal | publisher = American Geriatrics Society 2012 Beers Criteria Update Expert Panel | title = American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults | journal = Journal of the American Geriatrics Society | volume = 60 | issue = 4 | pages = 616–631 | date = April 2012 | pmid = 22376048 | pmc = 3571677 | doi = 10.1111/j.1532-5415.2012.03923.x | vauthors = Fick D, Semla T, Beizer J, Brandt N, Dombrowski R, DuBeau CE, Flanagan N, Hanlon J, Hollmann P, Linnebur S, Nau D, Rehm B, Sandhu S, Steinman M | collaboration = American Geriatrics Society 2012 Beers Criteria Update Expert Panel }}</ref>

===Seizures===
{{Further|Seizure}}
[[File:Diazepam 10mg-2ml vial yellow background.jpg|thumb|Diazepam 10mg/2ml vial]]

Prolonged convulsive [[epileptic seizure]]s are a [[medical emergency]] that can usually be dealt with effectively by administering fast-acting benzodiazepines, which are potent [[anticonvulsants]]. In a hospital environment, [[intravenous]] [[clonazepam]], [[lorazepam]], and [[diazepam]] are first-line choices. In the community, intravenous administration is not practical and so [[rectal]] diazepam or [[buccal mucosa|buccal]] [[midazolam]] are used, with a preference for midazolam as its administration is easier and more socially acceptable.<ref name=SIGN70>{{cite web |url=http://sign.ac.uk/pdf/sign70.pdf |title=Diagnosis and management of epilepsy in adults |access-date=5 June 2009 |publisher=Scottish Intercollegiate Guidelines Network |year=2005 |pages=17–19 |archive-url=https://web.archive.org/web/20090126152302/http://sign.ac.uk/pdf/sign70.pdf |archive-date=26 January 2009 |url-status=dead }}</ref><ref name=NICECG020>{{cite book |url=http://www.nice.org.uk/nicemedia/pdf/CG020fullguideline.pdf |archive-url=https://ghostarchive.org/archive/20221009/http://www.nice.org.uk/nicemedia/pdf/CG020fullguideline.pdf |archive-date=9 October 2022 |url-status=live |title=Clinical Guidelines and Evidence Review for the Epilepsies: diagnosis and management in adults and children in primary and secondary care |access-date=2 June 2009 |vauthors=Stokes T, Shaw EJ, Juarez-Garcia A, Camosso-Stefinovic J, Baker R |date=October 2004 |publisher=Royal College of General Practitioners |pages=61, 64–65 | location = London }}</ref>

When benzodiazepines were first introduced, they were enthusiastically adopted for treating all forms of [[epilepsy]]. However, drowsiness and [[drug tolerance|tolerance]] become problems with continued use and none are now considered [[first-line treatment|first-line]] choices for long-term epilepsy therapy.<ref name="pmid19298435">{{cite journal | vauthors = Shorvon SD | title = Drug treatment of epilepsy in the century of the ILAE: the second 50 years, 1959-2009 | journal = Epilepsia | volume = 50 | issue = Suppl 3 | pages = 93–130 | date = March 2009 | pmid = 19298435 | doi = 10.1111/j.1528-1167.2009.02042.x | s2cid = 20445985 | doi-access = free | title-link = doi }}</ref> [[Clobazam]] is widely used by specialist epilepsy clinics worldwide and clonazepam is popular in the Netherlands, Belgium and France.<ref name="pmid19298435"/> Clobazam was approved for use in the United States in 2011. In the UK, both clobazam and clonazepam are second-line choices for treating many forms of epilepsy.<ref name=NICECG020b>{{cite web |url=http://www.nice.org.uk/nicemedia/pdf/CG020fullguideline_appendixB.pdf |title=Clinical Guidelines and Evidence Review for the Epilepsies: diagnosis and management in adults and children in primary and secondary care (Appendix B) |access-date=2 June 2009 |vauthors=Stokes T, Shaw EJ, Juarez-Garcia A, Camosso-Stefinovic J, Baker R |date=October 2004 |publisher=Royal College of General Practitioners |page=432 |location=London |archive-url=https://web.archive.org/web/20111127113914/http://www.nice.org.uk/nicemedia/pdf/CG020fullguideline_appendixB.pdf |archive-date=27 November 2011 |url-status=dead }}</ref> Clobazam also has a useful role for very short-term seizure [[prophylaxis]] and in [[catamenial epilepsy]].<ref name="pmid19298435"/> Discontinuation after long-term use in epilepsy requires additional caution because of the risks of rebound seizures. Therefore, the dose is slowly tapered over a period of up to six months or longer.<ref name=NICECG020/>

===Alcohol withdrawal===
{{Further|Alcohol detoxification}}
[[File:Liverty 10mg.jpg|thumb|Chlordiazepoxide 10 mg pill]]

[[Chlordiazepoxide]] is the most commonly used benzodiazepine for [[alcohol detoxification]],<ref name="pmid9270461">{{cite journal | vauthors = Ashworth M, Gerada C | title = ABC of mental health. Addiction and dependence – II: Alcohol | journal = BMJ | volume = 315 | issue = 7104 | pages = 358–360 | date = August 1997 | pmid = 9270461 | pmc = 2127236 | doi = 10.1136/bmj.315.7104.358 }}</ref> but [[diazepam]] may be used as an alternative. Both are used in the detoxification of individuals who are motivated to stop drinking, and are prescribed for a short period of time to reduce the risks of developing tolerance and dependence to the benzodiazepine medication itself.<ref name="BNF_2009"/>{{rp|275|date=November 2012}} The benzodiazepines with a longer half-life make detoxification more tolerable, and dangerous (and potentially lethal) alcohol withdrawal effects are less likely to occur. On the other hand, short-acting benzodiazepines may lead to [[Causes of seizures#Breakthrough seizure|breakthrough seizures]], and are, therefore, not recommended for detoxification in an outpatient setting. [[Oxazepam]] and [[lorazepam]] are often used in patients at risk of drug accumulation, in particular, the elderly and those with [[cirrhosis]], because they are metabolized differently from other benzodiazepines, through [[Glucuronidation|conjugation]].<ref>{{cite journal | vauthors = Kraemer KL, Conigliaro J, Saitz R | title = Managing alcohol withdrawal in the elderly | journal = Drugs & Aging | volume = 14 | issue = 6 | pages = 409–425 | date = June 1999 | pmid = 10408740 | doi = 10.2165/00002512-199914060-00002 | s2cid = 2724630 }}</ref><ref>{{cite journal | vauthors = Prater CD, Miller KE, Zylstra RG | title = Outpatient detoxification of the addicted or alcoholic patient | journal = American Family Physician | volume = 60 | issue = 4 | pages = 1175–1183 | date = September 1999 | pmid = 10507746 }}</ref>

Benzodiazepines are the preferred choice in the management of [[alcohol withdrawal syndrome]], in particular, for the prevention and treatment of the dangerous complication of seizures and in subduing severe [[delirium]].<ref>{{cite journal | vauthors = Ebell MH | title = Benzodiazepines for alcohol withdrawal | journal = American Family Physician | volume = 73 | issue = 7 | pages = 1191 | date = April 2006 | pmid = 16623205 }}</ref> Lorazepam is the only benzodiazepine with predictable intramuscular absorption and it is the most effective in preventing and controlling acute seizures.<ref>{{cite journal | vauthors = Peppers MP | title = Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease | journal = Pharmacotherapy | volume = 16 | issue = 1 | pages = 49–57 | year = 1996 | pmid = 8700792 | doi = 10.1002/j.1875-9114.1996.tb02915.x | s2cid = 1389910 | url = https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/j.1875-9114.1996.tb02915.x | access-date = 1 February 2020 | archive-date = 15 January 2020 | archive-url = https://web.archive.org/web/20200115181651/https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/j.1875-9114.1996.tb02915.x | url-status = dead }}</ref>

===Other indications===
Benzodiazepines are often prescribed for a wide range of conditions:
* They can sedate patients receiving [[mechanical ventilation]] or those in extreme distress. Caution is exercised in this situation due to the risk of [[respiratory depression]], and it is recommended that [[benzodiazepine overdose]] treatment facilities should be available.<ref>{{cite journal | vauthors = Devlin JW, Roberts RJ | title = Pharmacology of commonly used analgesics and sedatives in the ICU: benzodiazepines, propofol, and opioids | journal = Critical Care Clinics | volume = 25 | issue = 3 | pages = 431–49, vii | date = July 2009 | pmid = 19576523 | doi = 10.1016/j.ccc.2009.03.003 }}</ref> They have also been found to increase the likelihood of later PTSD after people have been removed from ventilators.<ref>{{cite journal | vauthors = Parker AM, Sricharoenchai T, Raparla S, Schneck KW, Bienvenu OJ, Needham DM | title = Posttraumatic stress disorder in critical illness survivors: a metaanalysis | journal = Critical Care Medicine | volume = 43 | issue = 5 | pages = 1121–1129 | date = May 2015 | pmid = 25654178 | doi = 10.1097/CCM.0000000000000882 | s2cid = 11478971 }}</ref>
*Benzodiazepines are indicated in the management of breathlessness (shortness of breath) in advanced diseases, in particular where other treatments have failed to adequately control symptoms.<ref>{{cite journal | vauthors = Simon ST, Higginson IJ, Booth S, Harding R, Weingärtner V, Bausewein C | title = Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | pages = CD007354 | date = October 2016 | issue = 10 | pmid = 27764523 | pmc = 6464146 | doi = 10.1002/14651858.CD007354.pub3 }}</ref>
* Benzodiazepines are effective as medication given a couple of hours before surgery to relieve anxiety. They also produce [[amnesia]], which can be useful, as patients may not remember unpleasantness from the procedure.<ref name="Broscheit-2008">{{cite journal | vauthors = Broscheit J, Kranke P | title = [The preoperative medication: background and specific indications for the selection of the drugs] | journal = Anästhesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie | volume = 43 | issue = 2 | pages = 134–143 | date = February 2008 | pmid = 18293248 | doi = 10.1055/s-2008-1060547 | s2cid = 259982203 }}</ref> They are also used in patients with [[dental phobia]] as well as some ophthalmic procedures like refractive surgery; although such use is controversial and only recommended for those who are very anxious.<ref>{{cite journal | vauthors = Berthold C | title = Enteral sedation: safety, efficacy, and controversy | journal = Compendium of Continuing Education in Dentistry | volume = 28 | issue = 5 | pages = 264–271; quiz 272, 282 | date = May 2007 | pmid = 17607891 }}</ref> Midazolam is the most commonly prescribed for this use because of its strong sedative actions and fast recovery time, as well as its water solubility, which reduces pain upon injection. Diazepam and lorazepam are sometimes used. Lorazepam has particularly marked amnesic properties that may make it more effective when amnesia is the desired effect.<ref name="BNF_2009"/>{{rp|693|date=November 2012}}
* Benzodiazepines are well known for their strong muscle-relaxing properties and can be useful in the treatment of muscle spasms,<ref name="BNF_2009"/>{{rp|577–578|date=November 2012}} although tolerance often develops to their muscle relaxant effects.<ref name=tdamobd2004 /> [[Baclofen]]<ref>{{cite journal | vauthors = Mañon-Espaillat R, Mandel S | title = Diagnostic algorithms for neuromuscular diseases | journal = Clinics in Podiatric Medicine and Surgery | volume = 16 | issue = 1 | pages = 67–79 | date = January 1999 | doi = 10.1016/S0891-8422(23)00935-7 | pmid = 9929772 | s2cid = 12493035 }}</ref> or [[tizanidine]] are sometimes used as an alternative to benzodiazepines. Tizanidine has been found to have superior tolerability compared to diazepam and baclofen.<ref name="Kamen-2008">{{cite journal | vauthors = Kamen L, Henney HR, Runyan JD | title = A practical overview of tizanidine use for spasticity secondary to multiple sclerosis, stroke, and spinal cord injury | journal = Current Medical Research and Opinion | volume = 24 | issue = 2 | pages = 425–439 | date = February 2008 | pmid = 18167175 | doi = 10.1185/030079908X261113 | s2cid = 73086671 }}</ref>
* Benzodiazepines are also used to treat the acute panic caused by [[hallucinogen]] intoxication.<ref>{{cite book |vauthors=Wyatt JP, Illingworth RN, Robertson CE, Clancy MJ, Munro PT |title=Oxford Handbook of Accident and Emergency Medicine |edition=2nd |year=2005 |publisher=Oxford University Press |isbn=978-0-19-852623-0 |pages=173–208 |chapter=Poisoning }}</ref> Benzodiazepines are also used to calm the acutely agitated individual and can, if required, be given via an intramuscular injection.<ref>{{cite journal | vauthors = Zimbroff DL | title = Pharmacological control of acute agitation: focus on intramuscular preparations | journal = CNS Drugs | volume = 22 | issue = 3 | pages = 199–212 | year = 2008 | pmid = 18278976 | doi = 10.2165/00023210-200822030-00002 | s2cid = 73223621 }}</ref> They can sometimes be effective in the short-term treatment of psychiatric emergencies such as acute [[psychosis]] as in [[schizophrenia]] or [[mania]], bringing about rapid tranquillization and sedation until the effects of [[Lithium pharmacology|lithium]] or [[neuroleptics]] (antipsychotics) take effect. [[Lorazepam]] is most commonly used but [[clonazepam]] is sometimes prescribed for acute psychosis or mania;<ref>{{cite journal | vauthors = Curtin F, Schulz P | title = Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis | journal = Journal of Affective Disorders | volume = 78 | issue = 3 | pages = 201–208 | date = March 2004 | pmid = 15013244 | doi = 10.1016/S0165-0327(02)00317-8 }}</ref> their long-term use is not recommended due to risks of dependence.<ref name="BNF_2009"/>{{rp|204|date=November 2012}} Further research investigating the use of benzodiazepines alone and in combination with antipsychotic medications for treating acute psychosis is warranted.<ref>{{cite journal | vauthors = Gillies D, Sampson S, Beck A, Rathbone J | title = Benzodiazepines for psychosis-induced aggression or agitation | journal = Cochrane Database of Systematic Reviews | volume = 4 | issue = 4 | pages = CD003079 | date = April 2013 | pmid = 23633309 | doi = 10.1002/14651858.CD003079.pub3 | hdl = 10454/16512 | hdl-access = free }}</ref>
* [[Clonazepam]], a benzodiazepine is used to treat many forms of [[parasomnia]].<ref>{{cite journal | vauthors = Schenck CH, Arnulf I, Mahowald MW | title = Sleep and sex: what can go wrong? A review of the literature on sleep related disorders and abnormal sexual behaviors and experiences | journal = Sleep | volume = 30 | issue = 6 | pages = 683–702 | date = June 2007 | pmid = 17580590 | pmc = 1978350 | doi = 10.1093/sleep/30.6.683}}</ref> [[Rapid eye movement behavior disorder]] responds well to low doses of clonazepam.<ref name="pmid10996567">{{cite journal | vauthors = Ferini-Strambi L, Zucconi M | title = REM sleep behavior disorder | journal = Clinical Neurophysiology | volume = 111 | issue = Suppl 2 | pages = S136–140 | date = September 2000 | pmid = 10996567 | doi = 10.1016/S1388-2457(00)00414-4 | s2cid = 43692512 }}</ref><ref>{{cite journal | vauthors = Silber MH | title = Sleep disorders | journal = Neurologic Clinics | volume = 19 | issue = 1 | pages = 173–186 | date = February 2001 | pmid = 11471763 | doi = 10.1016/S0733-8619(05)70011-6 }}</ref> [[Restless legs syndrome]] can be treated using clonazepam as a third line treatment option as the use of clonazepam is still investigational.<ref>{{cite journal | author = Grupo Brasileiro de Estudos em Síndrome das Pernas Inquietas (GBE-SPI) | title = Síndrome das pernas inquietas: diagnóstico e tratamento. Opinião de especialistas brasileiros | trans-title = Restless legs syndrome: diagnosis and treatment. Opinion of Brazilian experts | language = pt | journal = Arquivos de Neuro-Psiquiatria | volume = 65 | issue = 3A | pages = 721–727 | date = September 2007 | pmid = 17876423 | doi = 10.1590/S0004-282X2007000400035 | doi-access = free | title-link = doi | hdl = 11449/69841 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Trenkwalder C, Hening WA, Montagna P, Oertel WH, Allen RP, Walters AS, Costa J, Stiasny-Kolster K, Sampaio C | title = Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice | journal = Movement Disorders | volume = 23 | issue = 16 | pages = 2267–2302 | date = December 2008 | pmid = 18925578 | doi = 10.1002/mds.22254 | s2cid = 91440 | url = http://www.movementdisorders.org/publications/ebm_reviews/treatmentofrls.pdf | access-date = 19 January 2010 | archive-url = https://web.archive.org/web/20091229102940/http://www.movementdisorders.org/publications/ebm_reviews/treatmentofrls.pdf | archive-date = 29 December 2009 | url-status=dead }}</ref>
* Benzodiazepines are sometimes used for [[obsessive–compulsive disorder]] (OCD), although they are generally believed ineffective for this indication. Effectiveness was, however, found in one small study.<ref>{{cite book | title = The American Psychiatric Publishing Textbook of Psychopharmacology | date = 2009 | edition = Fourth | publisher = American Psychiatric Publishing | url = https://books.google.com/books?id=Xx7iNGdV25IC&pg=PA470 | isbn = 978-1-58562-309-9 | page = 470 | veditors = Schatzberg AF, Nemeroff CB }}</ref> Benzodiazepines can be considered as a treatment option in treatment resistant cases.<ref>{{cite journal | vauthors = Bandelow B | title = The medical treatment of obsessive-compulsive disorder and anxiety | journal = CNS Spectrums | volume = 13 | issue = 9 Suppl 14 | pages = 37–46 | date = September 2008 | pmid = 18849910 | doi = 10.1017/S1092852900026924 | s2cid = 26691595 }}</ref>
* [[Antipsychotics]] are generally a first-line treatment for delirium; however, when [[delirium]] is caused by alcohol or sedative hypnotic [[Drug withdrawal|withdrawal]], benzodiazepines are a first-line treatment.<ref name="Attard-2008">{{cite journal | vauthors = Attard A, Ranjith G, Taylor D | title = Delirium and its treatment | journal = CNS Drugs | volume = 22 | issue = 8 | pages = 631–644 | date = August 2008 | pmid = 18601302 | doi = 10.2165/00023210-200822080-00002 | s2cid = 94743 }}</ref>
* There is some evidence that low doses of benzodiazepines reduce adverse effects of [[electroconvulsive therapy]].<ref name="pmid22531198">{{cite journal | vauthors = Gallegos J, Vaidya P, D'Agati D, Jayaram G, Nguyen T, Tripathi A, Trivedi JK, Reti IM | title = Decreasing adverse outcomes of unmodified electroconvulsive therapy: suggestions and possibilities | journal = The Journal of ECT | volume = 28 | issue = 2 | pages = 77–81 | date = June 2012 | pmid = 22531198 | doi = 10.1097/YCT.0b013e3182359314 | s2cid = 6423840 }}</ref>

==Contraindications==
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, [[alcoholism|alcohol]] or drug-dependent individuals and individuals with [[comorbid]] [[psychiatric disorders]].<ref>{{cite journal | vauthors = Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, Vennat B, Llorca PM, Eschalier A | title = Benzodiazepine dependence: focus on withdrawal syndrome | journal = Annales Pharmaceutiques Françaises | volume = 67 | issue = 6 | pages = 408–413 | date = November 2009 | pmid = 19900604 | doi = 10.1016/j.pharma.2009.07.001 }}</ref>

Because of their muscle relaxant action, benzodiazepines may cause [[hypoventilation|respiratory depression]] in susceptible individuals. For that reason, they are contraindicated in people with [[myasthenia gravis]], [[sleep apnea]], [[bronchitis]], and [[Chronic obstructive pulmonary disease|COPD]].<ref name="isbn0-683-30128-4"/><ref name="isbn0-444-50998-4"/> Caution is required when benzodiazepines are used in people with [[personality disorders]] or [[intellectual disability]] because of frequent [[paradoxical reactions]].<ref name="isbn0-683-30128-4"/><ref name="isbn0-444-50998-4"/> In [[major depressive disorder|major depression]], they may precipitate [[suicide|suicidal tendencies]]<ref>{{cite web |publisher=Committee on Safety of Medicines |year=1988 |url=http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=CON2024428&RevisionSelectionMethod=LatestReleased |format=PDF |title=Benzodiazepines, dependence and withdrawal symptoms |access-date=28 May 2009 |archive-url=https://web.archive.org/web/20120222015417/http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=CON2024428&RevisionSelectionMethod=LatestReleased |archive-date=22 February 2012 |url-status=dead }}</ref> and are sometimes used for suicidal overdoses.<ref name="isbn0-444-50998-4"/> Individuals with a history of excessive alcohol use or non-medical use of [[opioid]]s or [[barbiturate]]s should avoid benzodiazepines, as there is a risk of life-threatening interactions with these drugs.<ref name="isbn1-58829-211-8"/>

===Pregnancy===
{{See also|Long-term effects of benzodiazepines#Neonatal effects|l1=Effects of benzodiazepines on newborns}}

In the United States, the [[Food and Drug Administration (United States)|Food and Drug Administration]] has categorized benzodiazepines into either [[Pregnancy category|category D or X]] meaning potential for harm in the unborn has been demonstrated.<ref>{{cite book |vauthors=Roach SS, Ford SM |title=Introductory Clinical Pharmacology |chapter-url=https://archive.org/details/introductoryclin0000roac |chapter-url-access=registration |edition=8th |year=2006 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-7595-3 |page=[https://archive.org/details/introductoryclin0000roac/page/236 236] |chapter=Sedatives and hypnotics }}</ref>

Exposure to benzodiazepines during pregnancy has been associated with a slightly increased (from 0.06 to 0.07%) risk of [[cleft lip and palate|cleft palate]] in newborns, a controversial conclusion as some studies find no association between benzodiazepines and cleft palate. Their use by expectant mothers shortly before the delivery may result in a [[floppy infant syndrome]]. Newborns with this condition tend to have [[hypotonia]], [[hypothermia]], [[lethargy]], and breathing and feeding difficulties.<ref name=ACOG>{{cite journal | title = ACOG Practice Bulletin No. 92: Use of Psychiatric Medications During Pregnancy and Lactation | journal = Obstetrics and Gynecology | volume = 111 | issue = 4 | pages = 1001–1020 | date = April 2008 | pmid = 18378767 | doi = 10.1097/AOG.0b013e31816fd910 | author1 = ACOG Committee on Practice Bulletins--Obstetrics}}</ref><ref name=pmid9748174>{{cite journal | vauthors = Dolovich LR, Addis A, Vaillancourt JM, Power JD, Koren G, Einarson TR | title = Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies | journal = [[BMJ]] | volume = 317 | issue = 7162 | pages = 839–843 | date = September 1998 | pmid = 9748174 | pmc = 31092 | doi = 10.1136/bmj.317.7162.839 }}</ref> Cases of [[neonatal withdrawal syndrome]] have been described in infants chronically exposed to benzodiazepines [[Uterus|in utero]]. This syndrome may be hard to recognize, as it starts several days after delivery, for example, as late as 21 days for chlordiazepoxide. The symptoms include [[tremor]]s, [[hypertonia]], [[hyperreflexia]], [[hyperactivity]], and vomiting and may last for up to three to six months.<ref name=ACOG/><ref name=pmid9614425>{{cite journal | author = American Academy of Pediatrics Committee on Drugs | title = Neonatal drug withdrawal. American Academy of Pediatrics Committee on Drugs | journal = Pediatrics | volume = 101 | issue = 6 | pages = 1079–1088 | date = June 1998 | doi = 10.1542/peds.101.6.1079 | pmid = 9614425 | url = http://pediatrics.aappublications.org/cgi/reprint/101/6/1079.pdf }}</ref> Tapering down the dose during pregnancy may lessen its severity. If used in pregnancy, those benzodiazepines with a better and longer safety record, such as [[diazepam]] or [[chlordiazepoxide]], are recommended over potentially more harmful benzodiazepines, such as [[temazepam]]<ref>[http://www.rxlist.com/restoril-drug/warnings-precautions.htm Temazepam-Rxlist Pregnancy Category]@</ref> or [[triazolam]]. Using the lowest effective dose for the shortest period of time minimizes the risks to the unborn child.<ref>{{cite journal | vauthors = Iqbal MM, Sobhan T, Ryals T | title = Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant | journal = Psychiatric Services | volume = 53 | issue = 1 | pages = 39–49 | date = January 2002 | pmid = 11773648 | doi = 10.1176/appi.ps.53.1.39 | doi-access = free | title-link = doi }}</ref>

===Elderly===
The benefits of benzodiazepines are least and the risks are greatest in the elderly.<ref name=pmid18035234>{{cite journal | vauthors = Tariq SH, Pulisetty S | title = Pharmacotherapy for insomnia | journal = Clinics in Geriatric Medicine | volume = 24 | issue = 1 | pages = 93–105, vii | date = February 2008 | pmid = 18035234 | doi = 10.1016/j.cger.2007.08.009 }}</ref><ref>{{cite journal | vauthors = Bain KT | title = Management of chronic insomnia in elderly persons | journal = The American Journal of Geriatric Pharmacotherapy | volume = 4 | issue = 2 | pages = 168–192 | date = June 2006 | pmid = 16860264 | doi = 10.1016/j.amjopharm.2006.06.006 }}</ref> They are listed as a potentially inappropriate medication for older adults by the [[American Geriatrics Society]].<ref>{{cite web |title=American Geriatrics Society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults|url=https://www.guidelinecentral.com/summaries/american-geriatrics-society-2015-updated-beers-criteria-for-potentially-inappropriate-medication-use-in-older-adults/ |website=Guideline Central |publisher=American Geriatrics Society |access-date=1 December 2018}}</ref> The elderly are at an increased risk of [[drug dependence|dependence]] and are more sensitive to the adverse effects such as memory problems, daytime sedation, impaired motor coordination, and increased risk of motor vehicle accidents and falls,<ref name=pmid16156679>{{cite journal | vauthors = Allain H, Bentué-Ferrer D, Polard E, Akwa Y, Patat A | title = Postural instability and consequent falls and hip fractures associated with use of hypnotics in the elderly: a comparative review | journal = Drugs & Aging | volume = 22 | issue = 9 | pages = 749–765 | year = 2005 | pmid = 16156679 | doi = 10.2165/00002512-200522090-00004 | s2cid = 9296501 }}</ref> and an increased risk of [[hip fractures]].<ref name="pmid22566242">{{cite journal | vauthors = Khong TP, de Vries F, Goldenberg JS, Klungel OH, Robinson NJ, Ibáñez L, Petri H | title = Potential impact of benzodiazepine use on the rate of hip fractures in five large European countries and the United States | journal = Calcified Tissue International | volume = 91 | issue = 1 | pages = 24–31 | date = July 2012 | pmid = 22566242 | pmc = 3382650 | doi = 10.1007/s00223-012-9603-8 }}</ref> The [[long-term effects of benzodiazepines]] and [[benzodiazepine dependence]] in the elderly can resemble [[dementia]], depression, or [[anxiety syndromes]], and progressively worsens over time. Adverse effects on cognition can be mistaken for the effects of old age. The benefits of withdrawal include improved cognition, alertness, mobility, reduced risk of incontinence, and a reduced risk of falls and fractures. The success of gradual-tapering benzodiazepines is as great in the elderly as in younger people. Benzodiazepines should be prescribed to the elderly only with caution and only for a short period at low doses.<ref name="pmid15001721">{{cite journal | vauthors = Bogunovic OJ, Greenfield SF | title = Practical geriatrics: Use of benzodiazepines among elderly patients | journal = Psychiatric Services | volume = 55 | issue = 3 | pages = 233–235 | date = March 2004 | pmid = 15001721 | doi = 10.1176/appi.ps.55.3.233 }}</ref><ref name="prescribing_for_elderly_patients"/> Short to intermediate-acting benzodiazepines are preferred in the elderly such as [[oxazepam]] and [[temazepam]]. The high potency benzodiazepines [[alprazolam]] and [[triazolam]] and long-acting benzodiazepines are not recommended in the elderly due to increased adverse effects. [[Nonbenzodiazepines]] such as [[zaleplon]] and [[zolpidem]] and low doses of sedating antidepressants are sometimes used as alternatives to benzodiazepines.<ref name="prescribing_for_elderly_patients">{{cite book | vauthors = Jackson SG, Jansen P, Mangoni A | title = Prescribing for Elderly Patients | url = https://books.google.com/books?id=A38nZY3vp2wC | year= 2009 | publisher = Wiley | isbn = 978-0-470-02428-7 | pages = 47–48 }}</ref><ref>{{cite book | vauthors = Rosenthal TC, Williams M, Naughton BJ | title = Office care geriatrics | year = 2006 | publisher = Lippincott Williams Wilkins | location = Philadelphia | url = https://books.google.com/books?id=iyZfvfo-M2wC&pg=PA260 | isbn = 978-0-7817-6196-3 | pages = 260–262 }}</ref>

Long-term use of benzodiazepines is associated with increased risk of cognitive impairment and dementia, and reduction in prescribing levels is likely to reduce dementia risk.<ref name="pmid29926372">{{cite journal |vauthors=Penninkilampi R, Eslick GD |title=A Systematic Review and Meta-Analysis of the Risk of Dementia Associated with Benzodiazepine Use, After Controlling for Protopathic Bias |journal=CNS Drugs |volume= 32|issue= 6|pages= 485–497|date=June 2018 |pmid=29926372 |doi=10.1007/s40263-018-0535-3 |s2cid=49351844 }}</ref> The association of a history of benzodiazepine use and cognitive decline is unclear, with some studies reporting a lower risk of cognitive decline in former users, some finding no association and some indicating an increased risk of cognitive decline.<ref>{{cite journal | vauthors = Verdoux H, Lagnaoui R, Begaud B | title = Is benzodiazepine use a risk factor for cognitive decline and dementia? A literature review of epidemiological studies | journal = Psychological Medicine | volume = 35 | issue = 3 | pages = 307–315 | date = March 2005 | pmid = 15841867 | doi = 10.1017/S0033291704003897 | s2cid = 7774439 }}</ref>

Benzodiazepines are sometimes prescribed to treat behavioral symptoms of dementia. However, like [[antidepressant]]s, they have little evidence of effectiveness, although [[antipsychotic]]s have shown some benefit.<ref>{{cite journal | vauthors = Snowden M, Sato K, Roy-Byrne P | title = Assessment and treatment of nursing home residents with depression or behavioral symptoms associated with dementia: a review of the literature | journal = Journal of the American Geriatrics Society | volume = 51 | issue = 9 | pages = 1305–1317 | date = September 2003 | pmid = 12919245 | doi = 10.1046/j.1532-5415.2003.51417.x | s2cid = 2758628 }}</ref><ref>{{cite journal | vauthors = Wang PS, Brookhart MA, Setoguchi S, Patrick AR, Schneeweiss S | title = Psychotropic medication use for behavioral symptoms of dementia | journal = Current Neurology and Neuroscience Reports | volume = 6 | issue = 6 | pages = 490–495 | date = November 2006 | pmid = 17074284 | doi = 10.1007/s11910-006-0051-6 | s2cid = 39610712 }}</ref> Cognitive impairing effects of benzodiazepines that occur frequently in the elderly can also worsen dementia.<ref name="pmid10779253">{{cite journal | vauthors = Longo LP, Johnson B | title = Addiction: Part I. Benzodiazepines – side effects, abuse risk and alternatives | journal = American Family Physician | volume = 61 | issue = 7 | pages = 2121–2128 | date = April 2000 | pmid = 10779253 | url = http://www.aafp.org/afp/20000401/2121.html | access-date = 25 May 2008 | archive-date = 12 May 2008 | archive-url = https://web.archive.org/web/20080512180747/http://www.aafp.org/afp/20000401/2121.html | url-status = dead }}</ref>

==Adverse effects==
[[File:HarmCausedByDrugsTable.svg|thumb|upright=1.35|class=skin-invert-image|Table from the 2010 ISCD study ranking various drugs (legal and illegal) based on statements by drug-harm experts. Benzodiazepines were found to be the 10th most dangerous drug overall.<ref name="Nutt_2010">{{cite journal | vauthors = Nutt DJ, King LA, Phillips LD | title = Drug harms in the UK: a multicriteria decision analysis | journal = Lancet | volume = 376 | issue = 9752 | pages = 1558–1565 | date = November 2010 | pmid = 21036393 | doi = 10.1016/S0140-6736(10)61462-6 | s2cid = 5667719 | citeseerx = 10.1.1.690.1283 }}</ref>]]

{{See also|Long-term effects of benzodiazepines|Paradoxical reaction#Benzodiazepines|benzodiazepine withdrawal syndrome}}
The most common side-effects of benzodiazepines are related to their sedating and muscle-relaxing action. They include [[drowsiness]], dizziness, and decreased alertness and concentration. Lack of [[motor coordination|coordination]] may result in falls and injuries particularly in the elderly.<ref name="isbn0-683-30128-4">{{cite book |author=Ballenger JC |veditors=Sadock VA, Sadock BJ, Kaplan HI |title=Kaplan & Sadock's Comprehensive Textbook of Psychiatry |edition=7th |chapter=Benzodiazepine receptors agonists and antagonists |publisher=Lippincott Williams & Wilkins |pages=2317–2323 |year=2000 |isbn=978-0-683-30128-1 }}</ref><ref name="isbn0-470-02821-1">{{cite book |vauthors=Tasman A, Lieberman JA |title=Handbook of Psychiatric Drugs |publisher=Wiley |year=2006 |page=151 |isbn=978-0-470-02821-6 }}</ref><ref name="pmid18929314">{{cite journal | vauthors = Stone KL, Ensrud KE, Ancoli-Israel S | title = Sleep, insomnia and falls in elderly patients | journal = Sleep Medicine | volume = 9 | issue = Suppl 1 | pages = S18–22 | date = September 2008 | pmid = 18929314 | doi = 10.1016/S1389-9457(08)70012-1 | s2cid = 206134458 }}</ref> Another result is impairment of driving skills and increased likelihood of road traffic accidents.<ref>{{cite journal | vauthors = Rapoport MJ, Lanctôt KL, Streiner DL, Bédard M, Vingilis E, Murray B, Schaffer A, Shulman KI, Herrmann N | title = Benzodiazepine use and driving: a meta-analysis | journal = The Journal of Clinical Psychiatry | volume = 70 | issue = 5 | pages = 663–673 | date = May 2009 | pmid = 19389334 | doi = 10.4088/JCP.08m04325 }}</ref><ref>{{cite journal | vauthors = Orriols L, Salmi LR, Philip P, Moore N, Delorme B, Castot A, Lagarde E | title = The impact of medicinal drugs on traffic safety: a systematic review of epidemiological studies | journal = Pharmacoepidemiology and Drug Safety | volume = 18 | issue = 8 | pages = 647–658 | date = August 2009 | pmid = 19418468 | pmc = 2780583 | doi = 10.1002/pds.1763 }}</ref> Decreased libido and erection problems are a common side effect. Depression and [[disinhibition]] may emerge. [[Hypotension]] and suppressed breathing ([[hypoventilation]]) may be encountered with intravenous use.<ref name="isbn0-683-30128-4"/><ref name="isbn0-470-02821-1"/> Less common side effects include nausea and changes in appetite, blurred vision, confusion, [[euphoria (emotion)|euphoria]], [[depersonalization]] and nightmares. Cases of [[liver toxicity]] have been described but are very rare.<ref name="BNF_2009"/>{{rp|183–189|date=November 2012}}<ref>{{medicinenet|benzodiazepines-oral}}</ref>

The [[long-term effects of benzodiazepine]] use can include [[cognitive impairment]] as well as affective and behavioural problems. Feelings of turmoil, difficulty in thinking constructively, loss of sex-drive, [[agoraphobia]] and social phobia, increasing anxiety and depression, loss of interest in leisure pursuits and interests, and an inability to experience or express feelings can also occur. Not everyone, however, experiences problems with long-term use.<ref name="asapdacg">{{cite book |veditors=Haddad P, Dursun S, Deakin B |title=Adverse Syndromes and Psychiatric Drugs: A Clinical Guide |year=2004 |publisher=Oxford University Press |isbn=978-0-19-852748-0 |pages=239–260 |author=Ashton H |chapter=Benzodiazepine dependence }}</ref><ref>{{cite book |veditors=Palmer S, Dainow S, Milner P |title=Counselling: The BACP Counselling Reader |volume=1 |year=1996 |publisher=Sage |isbn=978-0-8039-7477-7 |pages=211–214 |chapter-url=https://books.google.com/books?id=wnIBEQKQi7IC |vauthors=Hammersley D, Beeley L |chapter=The effects of medication on counselling }}</ref> Additionally, an altered perception of self, environment and relationships may occur.<ref name="pmid15762814" /> A study published in 2020 found that long-term use of prescription benzodiazepines is associated with an increase in all-cause mortality among those age 65 or younger, but not those older than 65. The study also found that all-cause mortality was increased further in cases in which benzodiazepines are co-prescribed with opioids, relative to cases in which benzodiazepines are prescribed without opioids, but again only in those age 65 or younger.<ref>{{cite journal | vauthors = Xu KY, Hartz SM, Borodovsky JT, Bierut LJ, Grucza RA | title = Association Between Benzodiazepine Use With or Without Opioid Use and All-Cause Mortality in the United States, 1999-2015 | journal = JAMA Network Open | volume = 3 | issue = 12 | pages = e2028557 | date = December 2020 | pmid = 33295972 | pmc = 7726637 | doi = 10.1001/jamanetworkopen.2020.28557 }}</ref>

Compared to other sedative-hypnotics, visits to the hospital involving benzodiazepines had a 66% greater odds of a serious adverse health outcome. This included hospitalization, patient transfer, or death, and visits involving a combination of benzodiazepines and non-benzodiapine receptor agonists had almost four-times increased odds of a serious health outcome.<ref name=":0">{{cite journal | vauthors = Kaufmann CN, Spira AP, Alexander GC, Rutkow L, Mojtabai R | title = Emergency department visits involving benzodiazepines and non-benzodiazepine receptor agonists | journal = The American Journal of Emergency Medicine | volume = 35 | issue = 10 | pages = 1414–1419 | date = October 2017 | pmid = 28476551 | pmc = 5623103 | doi = 10.1016/j.ajem.2017.04.023 }}</ref>

In September 2020, the US [[Food and Drug Administration]] (FDA) required the [[boxed warning]] be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.<ref>{{citation-attribution|1={{cite web | title=FDA expands Boxed Warning to improve safe use of benzodiazepine drug | website=U.S. [[Food and Drug Administration]] (FDA) | date=23 September 2020 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class | access-date=23 September 2020}} }}</ref>

===Cognitive effects===
The short-term use of benzodiazepines adversely affects multiple areas of cognition, the most notable one being that it interferes with the formation and consolidation of memories of new material and may induce complete [[anterograde amnesia]].<ref name="isbn0-683-30128-4" /> However, researchers hold contrary opinions regarding the effects of long-term administration. One view is that many of the short-term effects continue into the long-term and may even worsen, and are not resolved after stopping benzodiazepine usage. Another view maintains that cognitive deficits in chronic benzodiazepine users occur only for a short period after the dose, or that the anxiety disorder is the cause of these deficits.

While the definitive studies are lacking, the former view received support from a 2004 meta-analysis of 13 small studies.<ref name="pmid15762814">{{cite journal | vauthors = Stewart SA | title = The effects of benzodiazepines on cognition | journal = The Journal of Clinical Psychiatry | volume = 66 | issue = Suppl 2 | pages = 9–13 | year = 2005 | pmid = 15762814 | url = http://psychiatrist.com/supplenet/v66s02/v66s0202.pdf | access-date = 14 June 2009 | archive-url = https://web.archive.org/web/20051213232324/http://psychiatrist.com/supplenet/v66s02/v66s0202.pdf | archive-date = 13 December 2005 | url-status=dead }}</ref><ref name="pmid14731058">{{cite journal | vauthors = Barker MJ, Greenwood KM, Jackson M, Crowe SF | title = Cognitive effects of long-term benzodiazepine use: a meta-analysis | journal = CNS Drugs | volume = 18 | issue = 1 | pages = 37–48 | year = 2004 | pmid = 14731058 | doi = 10.2165/00023210-200418010-00004 | s2cid = 15340907 }}</ref> This meta-analysis found that long-term use of benzodiazepines was associated with moderate to large adverse effects on all areas of cognition, with [[Spatial visualization ability|visuospatial]] memory being the most commonly detected impairment. Some of the other impairments reported were decreased IQ, visiomotor coordination, information processing, verbal learning and concentration. The authors of the meta-analysis<ref name="pmid14731058" /> and a later reviewer<ref name="pmid15762814" /> noted that the applicability of this meta-analysis is limited because the subjects were taken mostly from withdrawal clinics; the coexisting drug, alcohol use, and psychiatric disorders were not defined; and several of the included studies conducted the cognitive measurements during the withdrawal period.

=== Paradoxical effects ===
[[Paradoxical reactions]], such as increased seizures in epileptics,<ref name="Riss-2008">{{cite journal | vauthors = Riss J, Cloyd J, Gates J, Collins S | title = Benzodiazepines in epilepsy: pharmacology and pharmacokinetics | journal = Acta Neurologica Scandinavica | volume = 118 | issue = 2 | pages = 69–86 | date = August 2008 | pmid = 18384456 | doi = 10.1111/j.1600-0404.2008.01004.x | s2cid = 24453988 | doi-access = free | title-link = doi }}</ref> [[aggression]], violence, [[impulsivity]], [[irritability]] and suicidal behavior sometimes occur.<ref name="Dodds_2017" /> These reactions have been explained as consequences of disinhibition and the subsequent loss of control over socially unacceptable behavior. Paradoxical reactions are rare in the general population, with an incidence rate below 1% and similar to placebo.<ref name=pmid18922233>{{cite journal | vauthors = Saïas T, Gallarda T | title = [Paradoxical aggressive reactions to benzodiazepine use: a review] | language = fr | journal = L'Encéphale | volume = 34 | issue = 4 | pages = 330–336 | date = September 2008 | pmid = 18922233 | doi = 10.1016/j.encep.2007.05.005 }}</ref><ref name=badar2002>{{cite journal |publisher=Paton C |title=Benzodiazepines and disinhibition: a review |journal=The Psychiatrist |volume=26 |issue=12 |pages=460–462 |year=2002 |doi=10.1192/pb.26.12.460 |url=http://pb.rcpsych.org/cgi/reprint/26/12/460.pdf |archive-url=https://ghostarchive.org/archive/20221009/http://pb.rcpsych.org/cgi/reprint/26/12/460.pdf |archive-date=9 October 2022 |url-status=live | doi-access = free | title-link = doi | vauthors = Paton C }}</ref> However, they occur with greater frequency in recreational abusers, individuals with [[borderline personality disorder]], children, and patients on high-dosage regimes.<ref name="Bond_1998">{{cite journal |publisher=Bond AJ |title=Drug-induced behavioural disinhibition: incidence, mechanisms and therapeutic implications |journal=CNS Drugs |volume=9 |issue=1 |pages=41–57 |year=1998 |doi=10.2165/00023210-199809010-00005 |s2cid=140765796 }}</ref><ref name="Drummer_2002">{{cite journal | vauthors = Drummer OH | title = Benzodiazepines - Effects on Human Performance and Behavior | journal = Forensic Science Review | volume = 14 | issue = 1–2 | pages = 1–14 | date = February 2002 | pmid = 26256485 }}</ref> In these groups, [[impulse control]] problems are perhaps the most important risk factor for disinhibition; learning disabilities and neurological disorders are also significant risks. Most reports of disinhibition involve high doses of high-potency benzodiazepines.<ref name=badar2002 /> Paradoxical effects may also appear after chronic use of benzodiazepines.<ref name=cbpham>{{cite book |author=Ashton H |veditors=Ayers S, Baum A, McManus C, Newman S |title=Cambridge Handbook of Psychology, Health and Medicine |edition=2nd |year=2007 |publisher=Cambridge University Press |isbn=978-0-521-87997-2 |pages=675–8 |chapter=Drug dependency: benzodiazepines }}</ref>

===Long-term worsening of psychiatric symptoms===
While benzodiazepines may have short-term benefits for anxiety, sleep and agitation in some patients, long-term (i.e., greater than 2–4 weeks) use can result in a worsening of the very symptoms the medications are meant to treat. Potential explanations include exacerbating cognitive problems that are already common in anxiety disorders, causing or worsening [[Mood disorder#Substance-induced|depression]] and suicidality,<ref name="Michelini_1996" /><ref name="Lydiard_1996">{{cite journal | vauthors = Lydiard RB, Brawman-Mintzer O, Ballenger JC | title = Recent developments in the psychopharmacology of anxiety disorders | journal = Journal of Consulting and Clinical Psychology | volume = 64 | issue = 4 | pages = 660–608 | date = August 1996 | pmid = 8803355 | doi = 10.1037/0022-006x.64.4.660 }}</ref> disrupting sleep architecture by inhibiting deep stage sleep,<ref name="Psychiatry_2008" /> withdrawal symptoms or rebound symptoms in between doses mimicking or exacerbating underlying anxiety or sleep disorders,<ref name="Michelini_1996" /><ref name="Lydiard_1996" /> inhibiting the benefits of psychotherapy by inhibiting memory consolidation and reducing fear extinction,<ref>{{cite journal | vauthors = Gelpin E, Bonne O, Peri T, Brandes D, Shalev AY | title = Treatment of recent trauma survivors with benzodiazepines: a prospective study | journal = The Journal of Clinical Psychiatry | volume = 57 | issue = 9 | pages = 390–394 | date = September 1996 | pmid = 9746445 }}</ref><ref>{{cite journal | vauthors = Rosen CS, Greenbaum MA, Schnurr PP, Holmes TH, Brennan PL, Friedman MJ | title = Do benzodiazepines reduce the effectiveness of exposure therapy for posttraumatic stress disorder? | journal = The Journal of Clinical Psychiatry | volume = 74 | issue = 12 | pages = 1241–1248 | date = December 2013 | pmid = 24434093 | doi = 10.4088/JCP.13m08592 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Wilhelm FH, Roth WT | title = Acute and delayed effects of alprazolam on flight phobics during exposure | journal = Behaviour Research and Therapy | volume = 35 | issue = 9 | pages = 831–841 | date = September 1997 | pmid = 9299803 | doi = 10.1016/s0005-7967(97)00033-8 | doi-access = free | title-link = doi }}</ref> and reducing coping with trauma/stress and increasing vulnerability to future stress.<ref>{{cite journal | vauthors = Matar MA, Zohar J, Kaplan Z, Cohen H | title = Alprazolam treatment immediately after stress exposure interferes with the normal HPA-stress response and increases vulnerability to subsequent stress in an animal model of PTSD | journal = European Neuropsychopharmacology | volume = 19 | issue = 4 | pages = 283–295 | date = April 2009 | pmid = 19167197 | doi = 10.1016/j.euroneuro.2008.12.004 | s2cid = 93347 }}</ref> The latter two explanations may be why benzodiazepines are ineffective and/or potentially harmful in [[Post-traumatic stress disorder|PTSD]] and [[phobia]]s.<ref>{{cite book | vauthors = Taylor D, Barnes TR, Young AH | publisher = South London and Maudsley NHS Trust |url=https://www.worldcat.org/oclc/1250346653 |title=The Maudsley prescribing guidelines in psychiatry |date=2021 |isbn=978-1-119-77224-8 |edition=14th |location=Chichester, West Sussex |oclc=1250346653}}</ref> Anxiety, insomnia and irritability may be temporarily exacerbated during withdrawal, but psychiatric symptoms after discontinuation are usually less than even while taking benzodiazepines.<ref name="Michelini_1996" /><ref>{{cite journal | vauthors = Curran HV, Collins R, Fletcher S, Kee SC, Woods B, Iliffe S | title = Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life | journal = Psychological Medicine | volume = 33 | issue = 7 | pages = 1223–1237 | date = October 2003 | pmid = 14580077 | doi = 10.1017/s0033291703008213 | s2cid = 20586160 | url = http://discovery.ucl.ac.uk/14113/ }}</ref> Functioning significantly improves within 1 year of discontinuation.<ref name="Michelini_1996" /><ref>{{cite journal|title = Prescribing benzodiazepines in clinical practice|vauthors=Pary R, Lewis S |date = 2008|journal = Resident and Staff Physician |volume=54 |issue=1 |pages=8–17}}</ref>

===Physical dependence, withdrawal and post-withdrawal syndromes===
{{Main|Benzodiazepine dependence|Benzodiazepine withdrawal syndrome|post-acute withdrawal syndrome}}
[[Image:Diazepam2mgand5mgtablets.JPG|thumb|alt=White bottle with red and black labels on a blue pad atop a desk. Also on the pad are seven small pills.|[[Diazepam]] 2&nbsp;mg and 5&nbsp;mg diazepam tablets, which are commonly used in the treatment of [[benzodiazepine withdrawal]].]]

====Tolerance====
[[drug tolerance|Tolerance]] and [[physical dependence|dependence]] are risks of chronic benzodiazepine use, and can result in doses within the therapeutic range ceasing to offer meaningful symptomatic relief after prolonged use. Tolerance develops at different rates and to different degrees to the sedative, hypnotic, anticonvulsant, muscle relaxant and [[anxiolytic]] effects of benzodiazpines. A review<ref name=":2">{{cite journal | vauthors = Vinkers CH, Olivier B | title = Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABA(A) Receptor Modulators? | journal = Advances in Pharmacological Sciences | volume = 2012 | pages = 416864 | date = 2012 | pmid = 22536226 | pmc = 3321276 | doi = 10.1155/2012/416864 | doi-access = free }}</ref> of benzodiazepine tolerance concluded that it ''"appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all",'' although the included [[randomized controlled trial]] evidence<ref>{{cite journal | vauthors = Schweizer E, Rickels K, Weiss S, Zavodnick S | title = Maintenance drug treatment of panic disorder. I. Results of a prospective, placebo-controlled comparison of alprazolam and imipramine | journal = Archives of General Psychiatry | volume = 50 | issue = 1 | pages = 51–60 | date = January 1993 | pmid = 8422222 | doi = 10.1001/archpsyc.1993.01820130053009 }}</ref><ref name=":3">{{cite journal | vauthors = Rickels K, Case WG, Downing RW, Winokur A | title = Long-term diazepam therapy and clinical outcome | journal = JAMA | volume = 250 | issue = 6 | pages = 767–771 | date = August 1983 | pmid = 6348314 | doi = 10.1001/jama.1983.03340060045024 }}</ref> is limited to 22 weeks. A review of [[clonazepam]] in the treatment of psychiatric disorders concluded that there is longitudinal data supporting anxiolytic benefit without tolerance during long-term use,<ref name="pmid16528135">{{cite journal | vauthors = Nardi AE, Perna G | title = Clonazepam in the treatment of psychiatric disorders: an update | journal = International Clinical Psychopharmacology | volume = 21 | issue = 3 | pages = 131–142 | date = May 2006 | pmid = 16528135 | doi = 10.1097/01.yic.0000194379.65460.a6 | s2cid = 29469943 }}</ref> including an [[Open-label trial|open-label study]] finding continued benefit at 3 years.<ref name=":4">{{cite journal | vauthors = Nardi AE, Valença AM, Nascimento I, Lopes FL, Mezzasalma MA, Freire RC, Veras AB, Zin WA, Versiani M | title = A three-year follow-up study of patients with the respiratory subtype of panic disorder after treatment with clonazepam | journal = Psychiatry Research | volume = 137 | issue = 1–2 | pages = 61–70 | date = November 2005 | pmid = 16226812 | doi = 10.1016/j.psychres.2005.05.011 }}</ref> However, the review concludes that long-term [[Randomized controlled trial|RCT]] evidence is scant. A study of benzodiazepine sensitivity found that patients treated chronically with alprazolam did not differ from untreated patients in terms of anxiolytic response to diazepam, suggesting a lack of anxiolytic tolerance.<ref>{{cite journal | vauthors = Cowley DS, Roy-Byrne PP, Radant A, Ritchie JC, Greenblatt DJ, Nemeroff CB, Hommer DW | title = Benzodiazepine sensitivity in panic disorder: effects of chronic alprazolam treatment | journal = Neuropsychopharmacology | volume = 12 | issue = 2 | pages = 147–157 | date = April 1995 | pmid = 7779243 | doi = 10.1016/0893-133X(94)00074-A }}</ref>

However, controversy remains regarding tolerance to anxiolytic effects, with some publications reporting that there is little evidence of continued efficacy beyond 4–6 months<ref name="pmid10779253" /> or that dependence phenomena are common.<ref name="Perugi" /><ref name="cgftmamoa2004" /> However, some of these references were published prior to the in-depth scoping reviews of benzodiazepine tolerance, and lack citations of RCT evidence of tolerance. Studies reporting on voluntary benzodiazepine cessation and withdrawal include patient reports of tolerance and worsening anxiety.<ref name="tdamobd2004" />

The question of tolerance to the amnesic effects of benzodiazepines is, likewise, unclear.<ref name="pmid15762818">{{cite journal |vauthors=Otto MW, Bruce SE, Deckersbach T |year=2005 |title=Benzodiazepine use, cognitive impairment, and cognitive-behavioral therapy for anxiety disorders: issues in the treatment of a patient in need |url=http://psychiatrist.com/supplenet/v66s02/v66s0206.pdf |url-status=dead |journal=The Journal of Clinical Psychiatry |volume=66 |issue=Suppl 2 |pages=34–38 |pmid=15762818 |archive-url=https://web.archive.org/web/20051214010100/http://psychiatrist.com/supplenet/v66s02/v66s0206.pdf |archive-date=14 December 2005 |access-date=22 June 2009}}</ref> Some evidence suggests that partial tolerance does develop, and that, "memory impairment is limited to a narrow window within 90 minutes after each dose".<ref name="pmid15078112">{{cite journal |vauthors=Chouinard G |year=2004 |title=Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound |url=http://psychiatrist.com/supplenet/v65s05/v65s0502.pdf |url-status=dead |journal=The Journal of Clinical Psychiatry |volume=65 |issue=Suppl 5 |pages=7–12 |pmid=15078112 |archive-url=https://web.archive.org/web/20051213232617/http://psychiatrist.com/supplenet/v65s05/v65s0502.pdf |archive-date=13 December 2005 |access-date=22 June 2009}}</ref>

A major disadvantage of benzodiazepines is that tolerance to therapeutic effects develops relatively quickly while many adverse effects persist. Tolerance develops to hypnotic and myorelaxant effects within days to weeks, and to anticonvulsant effects within weeks to months.<ref name="Michelini_1996">{{cite journal|title = Long-term use of benzodiazepines: tolerance, dependence and clinical problems in anxiety and mood disorders|vauthors=Michelini S, Cassano GB, Frare F |date = 1996|journal = Pharmacopsychiatry |volume=29 |issue = 4|pages=127–134 |doi=10.1055/s-2007-979558 |pmid = 8858711|s2cid=19145509 |display-authors=etal}}</ref> Therefore, benzodiazepines are unlikely to be effective long-term treatments for sleep. While BZD therapeutic effects may disappear with tolerance, depression and impulsivity with high suicidal risk commonly persist.<ref name="Michelini_1996" /> Several studies have confirmed that long-term benzodiazepines are not significantly different from placebo for sleep,<ref>{{cite journal | vauthors = Curran HV, Collins R, Fletcher S, Kee SC, Woods B, Iliffe S | title = Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life | journal = Psychological Medicine | volume = 33 | issue = 7 | pages = 1223–1237 | date = October 2003 | pmid = 14580077 | doi = 10.1017/s0033291703008213 | s2cid = 20586160 | url = http://discovery.ucl.ac.uk/14113/1/14113.pdf }}</ref><ref>{{cite journal | vauthors = Holbrook AM | title = Treating insomnia| pmid = 15550406 | doi=10.1136/bmj.329.7476.1198 | volume=329 | issue = 7476| pmc=529353 | year=2004 | journal=BMJ | pages=1198–1199}}</ref><ref>{{cite journal | vauthors = Poyares D, Guilleminault C, Ohayon MM, Tufik S | title = Chronic benzodiazepine usage and withdrawal in insomnia patients | journal = Journal of Psychiatric Research | volume = 38 | issue = 3 | pages = 327–334 | date = 1 June 2004 | pmid = 15003439 | doi = 10.1016/j.jpsychires.2003.10.003 }}</ref> and question their use for anxiety disorders such as PTSD and OCD.<ref name="Michelini_1996" /><ref>{{cite journal|title = Pharmacotherapy for posttraumatic stress disorder: a status report| vauthors = Friedman MJ |date = 1998|journal = Psychiatry and Clinical Neurosciences |volume=52 |pages=S115–S121 |doi=10.1046/j.1440-1819.1998.0520s5S115.x |s2cid = 142421768}}</ref><ref>{{cite journal|title = Randomised controlled trial of two brief interventions against long-term benzodiazepine use: outcome of intervention|vauthors=Heather N, Bowie A, Ashton H, McAvoy B, Spencer I, Brodie J, Giddings D |date = 2004|journal = Addiction Research & Theory |volume=12 |issue=2 |pages=141–154|doi = 10.1080/1606635310001634528|s2cid = 59516280}}</ref><ref>{{cite journal | vauthors = Bandelow B, Zohar J, Hollander E, Kasper S, Möller HJ, Zohar J, Hollander E, Kasper S, Möller HJ, Bandelow B, Allgulander C, Ayuso-Gutierrez J, Baldwin DS, Buenvicius R, Cassano G, Fineberg N, Gabriels L, Hindmarch I, Kaiya H, Klein DF, Lader M, Lecrubier Y, Lépine JP, Liebowitz MR, Lopez-Ibor JJ, Marazziti D, Miguel EC, Oh KS, Preter M, Rupprecht R, Sato M, Starcevic V, Stein DJ, van Ameringen M, Vega J | title = World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders – first revision | journal = The World Journal of Biological Psychiatry | volume = 9 | issue = 4 | pages = 248–312 | date = 1 January 2008 | pmid = 18949648 | doi = 10.1080/15622970802465807 | s2cid = 39027026 | doi-access = free | title-link = doi }}</ref> This may explain why patients commonly increase doses over time and many eventually take more than one type of benzodiazepine after the first loses effectiveness.<ref name="Psychiatry_2008">{{cite book | title = Psychiatry | edition = 3rd | veditors = Tasman A, Kay J, Lieberman JA | publisher = John Wiley & Sons|year = 2008|isbn = 978-0-470-06571-6|location = Chichester, England|pages = 1186–1200, 2603–2615}}</ref><ref>{{cite journal | vauthors = Ashton H | s2cid = 1709063 | title = The diagnosis and management of benzodiazepine dependence | journal = Current Opinion in Psychiatry | volume = 18 | issue = 3 | pages = 249–255 | date = May 2005 | pmid = 16639148 | doi = 10.1097/01.yco.0000165594.60434.84 }}</ref><ref>{{cite journal | vauthors = Morin CM, Bélanger L, Bastien C, Vallières A | title = Long-term outcome after discontinuation of benzodiazepines for insomnia: a survival analysis of relapse | journal = Behaviour Research and Therapy | volume = 43 | issue = 1 | pages = 1–14 | date = January 2005 | pmid = 15531349 | doi = 10.1016/j.brat.2003.12.002 }}</ref> Additionally, because tolerance to benzodiazepine sedating effects develops more quickly than does tolerance to brainstem depressant effects, those taking more benzodiazepines to achieve desired effects may experience sudden respiratory depression, hypotension or death.<ref name="DSM-5">{{cite book | author = American Psychiatry Association | title = Diagnostic and statistical manual of mental disorders : DSM-5 | date = 2013 | publisher = American Psychiatric Publishing | location = Washington | isbn = 978-0-89042-555-8 | edition = 5th | url-access = registration | url = https://archive.org/details/diagnosticstatis0005unse }}</ref> Most patients with anxiety disorders and PTSD have symptoms that persist for at least several months,<ref name="DSM-5" /> making tolerance to therapeutic effects a distinct problem for them and necessitating the need for more effective long-term treatment (e.g., psychotherapy, serotonergic antidepressants).

====Withdrawal symptoms and management====
[[File:Chlordiazepoxidetabletsgeneric.JPG|thumb|alt=White bottle on blue pad atop a desk. The bottle cap is off, and is upside down on the pad in front of the bottle. In the cap are a dozen black-and-yellow capsules.|[[Chlordiazepoxide]] 5&nbsp;mg capsules, which are sometimes used as an alternative to [[diazepam]] for [[benzodiazepine withdrawal]]. Like diazepam it has a long [[elimination half-life]] and long-acting [[active metabolites]].]]

Discontinuation of benzodiazepines or abrupt reduction of the dose, even after a relatively short course of treatment (two to four weeks), may result in two groups of symptoms, [[Rebound effect|rebound]] and [[benzodiazepine withdrawal syndrome|withdrawal]]. Rebound symptoms are the return of the symptoms for which the patient was treated but worse than before. Withdrawal symptoms are the new symptoms that occur when the benzodiazepine is stopped. They are the main sign of [[physical dependence]].<ref name="pmid15078112" />

The most frequent symptoms of withdrawal from benzodiazepines are insomnia, gastric problems, [[tremor]]s, agitation, fearfulness, and [[Spasm|muscle spasms]].<ref name="pmid15078112" /> The less frequent effects are irritability, sweating, [[depersonalization]], [[derealization]], hypersensitivity to stimuli, depression, [[suicidal]] behavior, [[psychosis]], [[seizures]], and [[delirium tremens]].<ref name="isbn0-19-856667-0">{{cite book |vauthors=Harrison PC, Gelder MG, Cowen P |title=Shorter Oxford Textbook of Psychiatry |edition=5th |publisher=Oxford University Press |year=2006 |pages=461–462 |chapter=The misuse of alcohol and drugs |isbn=978-0-19-856667-0 }}</ref> Severe symptoms usually occur as a result of abrupt or over-rapid withdrawal. Abrupt withdrawal can be dangerous and lead to [[excitotoxicity]], causing damage and even death to nerve cells as a result of excessive levels of the excitatory neurotransmitter [[glutamate (neurotransmitter)|glutamate]]. Increased glutamatergic activity is thought to be part of a compensatory mechanism to chronic GABAergic inhibition from benzodiazepines.<ref name="gaba-glutamate-adapt">{{cite journal | vauthors = Allison C, Pratt JA | title = Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence| journal = Pharmacology & Therapeutics | volume = 98 | issue = 2 | pages = 171–195 | date = May 2003 | pmid = 12725868 | doi = 10.1016/s0163-7258(03)00029-9 }}</ref><ref name="gabaa-dependence">{{cite journal | vauthors = Cheng T, Wallace DM, Ponteri B, Tuli M | title = Valium without dependence? Individual GABAA receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects | journal = Neuropsychiatric Disease and Treatment | volume = 14 | issue = 1 | pages = 1351–1361 | date = 23 May 2018 | pmid = 29872302 | doi = 10.2147/NDT.S164307 | pmc = 5973310 | doi-access = free | title-link = doi }}</ref> Therefore, a gradual reduction regimen is recommended.<ref name="pmid19062773">{{cite journal | vauthors = Lader M, Tylee A, Donoghue J | title = Withdrawing benzodiazepines in primary care | journal = CNS Drugs | volume = 23 | issue = 1 | pages = 19–34 | year = 2009 | pmid = 19062773 | doi = 10.2165/0023210-200923010-00002 | s2cid = 113206 }}</ref>

Symptoms may also occur during a gradual dosage reduction, but are typically less severe and may persist as part of a protracted [[Benzodiazepine withdrawal syndrome|withdrawal syndrome]] for months after cessation of benzodiazepines.<ref name="isbn0-19-852518-4">{{cite book | vauthors = Collier J, Longmore M, Amarakone K | title = Oxford Handbook of Clinical Specialties|chapter-url=https://books.google.com/books?id=HCxoAgAAQBAJ&pg=PA368|year= 2013|publisher=OUP Oxford|isbn=978-0-19-150476-1|page=368 |chapter=Psychiatry }}</ref> Approximately 10% of patients experience a notable protracted withdrawal syndrome, which can persist for many months or in some cases a year or longer. Protracted symptoms tend to resemble those seen during the first couple of months of withdrawal but usually are of a sub-acute level of severity. Such symptoms do gradually lessen over time, eventually disappearing altogether.<ref name=pmid1675688>{{cite journal | vauthors = Ashton H | title = Protracted withdrawal syndromes from benzodiazepines | journal = Journal of Substance Abuse Treatment | volume = 8 | issue = 1–2 | pages = 19–28 | year = 1991 | pmid = 1675688 | doi = 10.1016/0740-5472(91)90023-4 | url = http://benzo.org.uk/ashpws.htm }}</ref>

Benzodiazepines have a reputation with patients and doctors for causing a severe and traumatic withdrawal; however, this is in large part due to the withdrawal process being poorly managed. Over-rapid withdrawal from benzodiazepines increases the severity of the withdrawal syndrome and increases the failure rate. A slow and gradual [[Drug withdrawal|withdrawal]] customised to the individual and, if indicated, psychological support is the most effective way of managing the withdrawal. Opinion as to the time needed to complete withdrawal ranges from four weeks to several years. A goal of less than six months has been suggested,<ref name=pmid19062773 /> but due to factors such as dosage and type of benzodiazepine, reasons for prescription, lifestyle, personality, [[environmental stresses]], and amount of available support, a year or more may be needed to withdraw.<ref name=tdamobd2004 /><ref name="BNF_2009"/>{{rp|183–184|date=November 2012}}

Withdrawal is best managed by transferring the physically dependent patient to an equivalent dose of diazepam because it has the longest half-life of all of the benzodiazepines, is metabolised into long-acting active metabolites and is available in low-potency tablets, which can be quartered for smaller doses.<ref name="manual" /> A further benefit is that it is available in liquid form, which allows for even smaller reductions.<ref name=pmid19062773/> [[Chlordiazepoxide]], which also has a long half-life and long-acting [[active metabolites]], can be used as an alternative.<ref name="manual">{{cite book |url=http://benzo.org.uk/manual/ |title=Benzodiazepines: how they work & how to withdraw (aka The Ashton Manual) |publisher=Ashton CH |year=2002 |access-date=27 May 2009 }}</ref><ref>{{cite book |vauthors=Lal R, Gupta S, Rao R, Kattimani S |title=Substance Use Disorder |url=http://www.whoindia.org/en/Section20/Section22_1674.htm |access-date=6 June 2009 |year=2007 |publisher=[[World Health Organization]] (WHO) |page=82 |chapter=Emergency management of substance overdose and withdrawal |chapter-url=http://www.whoindia.org/LinkFiles/Mental_Health_&_substance_Abuse_Emergency_management_of_Substance_Overdose_and_Withdrawal-Manual_For_Nursing_Personnel.pdf |quote=Generally, a longer-acting benzodiazepine such as chlordiazepoxide or diazepam is used and the initial dose titrated downward |archive-url=https://web.archive.org/web/20100613203853/http://whoindia.org/LinkFiles/Mental_Health_%26_substance_Abuse_Emergency_management_of_Substance_Overdose_and_Withdrawal-Manual_For_Nursing_Personnel.pdf |archive-date=13 June 2010 |url-status=dead }}</ref>

[[Nonbenzodiazepine]]s are contraindicated during benzodiazepine withdrawal as they are [[cross tolerant]] with benzodiazepines and can induce dependence.<ref name=tdamobd2004 /> Alcohol is also cross tolerant with benzodiazepines and more toxic and thus caution is needed to avoid replacing one dependence with another.<ref name="manual" /> During withdrawal, [[fluoroquinolone]]-based antibiotics are best avoided if possible; they displace benzodiazepines from their binding site and reduce GABA function and, thus, may aggravate withdrawal symptoms.<ref>{{cite web | url = http://www.smmgp.org.uk/download/guidance/guidance025.pdf | title = Guidance for the use and reduction of misuse of benzodiazepines and other hypnotics and anxiolytics in general practice | vauthors = Ford C, Law F | date = July 2014 | website = smmgp.org.uk | access-date = 18 October 2015 | archive-url = https://web.archive.org/web/20170706085219/http://www.smmgp.org.uk/download/guidance/guidance025.pdf | archive-date = 6 July 2017 | url-status = dead }}</ref> Antipsychotics are not recommended for benzodiazepine withdrawal (or other CNS depressant withdrawal states) especially [[clozapine]], [[olanzapine]] or low potency [[phenothiazines]], e.g., [[chlorpromazine]] as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required.<ref>{{cite book | vauthors = Ebadi M | title = Desk Reference for Clinical Pharmacology |chapter-url=https://books.google.com/books?id=ihxyHbnj3qYC |edition=2nd |year= 2007 |publisher=CRC Press |location=US|isbn=978-1-4200-4743-1 |page=512 |chapter=Alphabetical presentation of drugs }}</ref>

Withdrawal from long term benzodiazepines is beneficial for most individuals.<ref name=cbpham /> Withdrawal of benzodiazepines from long-term users, in general, leads to improved physical and [[mental health]] particularly in the elderly; although some long term users report continued benefit from taking benzodiazepines, this may be the result of suppression of withdrawal effects.<ref name=tdamobd2004 /><ref name=asapdacg/>

=== Controversial associations ===
Beyond the well established link between benzodiazepines and psychomotor impairment resulting in motor vehicle accidents and falls leading to fracture; research in the 2000s and 2010s has raised the association between benzodiazepines (and [[Z-drugs]]) and other, as of yet unproven, adverse effects including dementia, cancer, infections, pancreatitis and respiratory disease exacerbations.<ref>{{cite journal | vauthors = Brandt J, Leong C | title = Benzodiazepines and Z-Drugs: An Updated Review of Major Adverse Outcomes Reported on in Epidemiologic Research | journal = Drugs in R&D | volume = 17 | issue = 4 | pages = 493–507 | date = December 2017 | pmid = 28865038 | doi = 10.1007/s40268-017-0207-7 | pmc=5694420}}</ref>

==== Dementia ====
A number of studies have drawn an association between long-term benzodiazepine use and neuro-degenerative disease, particularly Alzheimer's disease.<ref>{{cite journal | vauthors = Zhong G, Wang Y, Zhang Y, Zhao Y | title = Association between Benzodiazepine Use and Dementia: A Meta-Analysis | journal = PLOS ONE | volume = 10 | issue = 5 | pages = e0127836 | date = 27 May 2015 | pmid = 26016483 | doi = 10.1371/journal.pone.0127836 | pmc=4446315| bibcode = 2015PLoSO..1027836Z | doi-access = free | title-link = doi }}</ref> It has been determined that long-term use of benzodiazepines is associated with increased dementia risk, even after controlling for [[protopathic bias]].<ref name="pmid29926372"/>

==== Infections ====
Some observational studies have detected significant associations between benzodiazepines and respiratory infections such as pneumonia<ref>{{cite journal | vauthors = Nakafero G, Sanders RD, Nguyen-Van-Tam JS, Myles PR | title = The association between benzodiazepines and influenza-like illness-related pneumonia and mortality: a survival analysis using UK Primary Care data | journal = Pharmacoepidemiology and Drug Safety | volume = 25 | issue = 11 | pages = 1263–1273 | date = November 2016 | pmid = 27215827 | doi = 10.1002/pds.4028 | s2cid = 24289824 | url = http://eprints.nottingham.ac.uk/34139/1/Nakafero_et_al-2016-Pharmacoepidemiology_and_Drug_Safety.pdf | access-date = 13 July 2019 | archive-date = 22 July 2018 | archive-url = https://web.archive.org/web/20180722195105/http://eprints.nottingham.ac.uk/34139/1/Nakafero_et_al-2016-Pharmacoepidemiology_and_Drug_Safety.pdf | url-status = dead }}</ref><ref>{{cite journal | vauthors = Obiora E, Hubbard R, Sanders RD, Myles PR | title = The impact of benzodiazepines on occurrence of pneumonia and mortality from pneumonia: a nested case-control and survival analysis in a population-based cohort | journal = Thorax | volume = 68 | issue = 2 | pages = 163–170 | date = February 2013 | pmid = 23220867 | doi = 10.1136/thoraxjnl-2012-202374 | s2cid = 7021626 | doi-access = free | title-link = doi }}</ref> where others have not.<ref>{{cite journal | vauthors = Dublin S, Walker RL, Jackson ML, Nelson JC, Weiss NS, Von Korff M, Jackson LA | title = Use of opioids or benzodiazepines and risk of pneumonia in older adults: a population-based case-control study | journal = Journal of the American Geriatrics Society | volume = 59 | issue = 10 | pages = 1899–1907 | date = October 2011 | pmid = 22091503 | doi = 10.1111/j.1532-5415.2011.03586.x | pmc=3223721}}</ref> A large meta-analysis of pre-marketing randomized controlled trials on the pharmacologically related Z-Drugs suggest a small increase in infection risk as well.<ref>{{cite journal | vauthors = Joya FL, Kripke DF, Loving RT, Dawson A, Kline LE | title = Meta-analyses of hypnotics and infections: eszopiclone, ramelteon, zaleplon, and zolpidem | journal = Journal of Clinical Sleep Medicine | volume = 5 | issue = 4 | pages = 377–383 | date = August 2009 | pmid = 19968019 | pmc = 2725260 | doi = 10.5664/jcsm.27552 }}</ref> An immunodeficiency effect from the action of benzodiazepines on GABA-A receptors has been postulated from animal studies.<ref>{{cite journal | vauthors = Sanders RD, Godlee A, Fujimori T, Goulding J, Xin G, Salek-Ardakani S, Snelgrove RJ, Ma D, Maze M, Hussell T | title = Benzodiazepine augmented γ-amino-butyric acid signaling increases mortality from pneumonia in mice | journal = Critical Care Medicine | volume = 41 | issue = 7 | pages = 1627–1636 | date = July 2013 | pmid = 23478657 | doi = 10.1097/ccm.0b013e31827c0c8d | pmc=5774585}}</ref><ref>{{cite journal | vauthors = Galdiero F, Bentivoglio C, Nuzzo I, Ianniello R, Capasso C, Mattera S, Nazzaro C, Galdiero M, Romano Carratelli C | title = Effects of benzodiazepines on immunodeficiency and resistance in mice | journal = Life Sciences | volume = 57 | issue = 26 | pages = 2413–2423 | date = November 1995 | pmid = 8847962 | doi = 10.1016/0024-3205(95)02199-0 }}</ref>

==== Cancer ====
A meta-analysis of observational studies has determined an association between benzodiazepine use and cancer, though the risk across different agents and different cancers varied significantly.<ref name="Use of benzodiazepine and risk of c"/> In terms of experimental basic science evidence, an analysis of carcinogenetic and genotoxicity data for various benzodiazepines has suggested a small possibility of carcinogenesis for a small number of benzodiazepines.<ref>{{cite journal | vauthors = Brambilla G, Carrozzino R, Martelli A | title = Genotoxicity and carcinogenicity studies of benzodiazepines | journal = Pharmacological Research | volume = 56 | issue = 6 | pages = 443–458 | date = December 2007 | pmid = 17920927 | doi = 10.1016/j.phrs.2007.08.006 }}</ref>

==== Pancreatitis ====
The evidence suggesting a link between benzodiazepines (and Z-Drugs) and pancreatic inflammation is very sparse and limited to a few observational studies from [[Taiwan]].<ref>{{cite journal | vauthors = Liaw GW, Hung DZ, Chen WK, Lin CL, Lin IC, Kao CH | title = Relationship Between Acute Benzodiazepine Poisoning and Acute Pancreatitis Risk: A Population-Based Cohort Study | journal = Medicine | volume = 94 | issue = 52 | pages = e2376 | date = December 2015 | pmid = 26717383 | doi = 10.1097/md.0000000000002376 | pmc=5291624}}</ref><ref>{{cite journal | vauthors = Lai SW, Lai HC, Lin CL, Liao KF | title = Zopiclone use associated with increased risk of acute pancreatitis: a case-control study in Taiwan | journal = International Journal of Clinical Practice | volume = 69 | issue = 11 | pages = 1275–1280 | date = November 2015 | pmid = 26133234 | doi = 10.1111/ijcp.12689 | s2cid = 26126233 | doi-access = free | title-link = doi }}</ref> A criticism of confounding can be applied to these findings as with the other controversial associations above. Further well-designed research from other populations as well as a biologically plausible mechanism is required to confirm this association.

==Overdose==
{{main|Benzodiazepine overdose}}
Although benzodiazepines are much safer in overdose than their predecessors, the [[barbiturate]]s, they can still cause problems in overdose.<ref name=pmid9780123>{{cite journal | vauthors = Fraser AD | title = Use and abuse of the benzodiazepines | journal = Therapeutic Drug Monitoring | volume = 20 | issue = 5 | pages = 481–489 | date = October 1998 | pmid = 9780123 | doi = 10.1097/00007691-199810000-00007 | pmc = 2536139 }}</ref> Taken alone, they rarely cause severe complications in [[Drug overdose|overdose]];<ref>{{cite journal | vauthors = Gaudreault P, Guay J, Thivierge RL, Verdy I | title = Benzodiazepine poisoning. Clinical and pharmacological considerations and treatment | journal = Drug Safety | volume = 6 | issue = 4 | pages = 247–265 | year = 1991 | pmid = 1888441 | doi = 10.2165/00002018-199106040-00003 | s2cid = 27619795 }}</ref> statistics in England showed that benzodiazepines were responsible for 3.8% of all deaths by poisoning from a single drug.<ref name=Charlson_2009/> However, combining these drugs with [[Ethanol|alcohol]], [[opiates]] or [[tricyclic antidepressants]] markedly raises the toxicity.<ref name=pmid10707430>{{cite journal | vauthors = White JM, Irvine RJ | title = Mechanisms of fatal opioid overdose | journal = Addiction | volume = 94 | issue = 7 | pages = 961–972 | date = July 1999 | pmid = 10707430 | doi = 10.1046/j.1360-0443.1999.9479612.x }}</ref><ref>{{cite web |publisher=Robin Mantooth |title=Toxicity, benzodiazepine |url=http://emedicine.medscape.com/article/813255-overview |website=eMedicine |date=28 January 2010 |access-date=2 October 2010 }}</ref><ref name=ohoam>{{cite book |vauthors=Ramrakha P, Moore K |title=Oxford Handbook of Acute Medicine |edition=2nd |year=2004 |publisher=Oxford University Press |pages=791–838 (798) |chapter=Chapter 14: Drug overdoses |isbn=978-0-19-852072-6 }}</ref> The elderly are more sensitive to the side effects of benzodiazepines, and poisoning may even occur from their long-term use.<ref>{{cite journal | vauthors = Klein-Schwartz W, Oderda GM | title = Poisoning in the elderly. Epidemiological, clinical and management considerations | journal = Drugs & Aging | volume = 1 | issue = 1 | pages = 67–89 | date = January 1991 | pmid = 1794007 | doi = 10.2165/00002512-199101010-00008 | s2cid = 13121885 }}</ref> The various benzodiazepines differ in their toxicity; [[temazepam]] appears most toxic in overdose and when used with other drugs.<ref>{{cite journal | vauthors = Buckley NA, Dawson AH, Whyte IM, O'Connell DL | title = Relative toxicity of benzodiazepines in overdose | journal = [[BMJ]] | volume = 310 | issue = 6974 | pages = 219–221 | date = January 1995 | pmid = 7866122 | pmc = 2548618 | doi = 10.1136/bmj.310.6974.219 }}</ref><ref>{{cite journal | vauthors = Serfaty M, Masterton G | title = Fatal poisonings attributed to benzodiazepines in Britain during the 1980s | journal = British Journal of Psychiatry | volume = 163 | issue = 1 | pages = 386–393 | date = September 1993 | pmid = 8104653 | doi = 10.1192/bjp.163.3.386 | s2cid = 46001278 }}</ref> The symptoms of a benzodiazepine overdose may include; [[drowsiness]], [[slurred speech]], [[nystagmus]], [[hypotension]], [[ataxia]], coma, [[respiratory depression]], and [[cardiorespiratory arrest]].<ref name=ohoam />

A reversal agent for benzodiazepines exists, [[flumazenil]] (Anexate), itself belonging to the chemical class of benzodiazepines. Its use as an [[antidote]] is not routinely recommended because of the high risk of resedation and seizures.<ref>{{cite journal | vauthors = Seger DL | title = Flumazenil – treatment or toxin | journal = Journal of Toxicology: Clinical Toxicology | volume = 42 | issue = 2 | pages = 209–216 | year = 2004 | pmid = 15214628 | doi = 10.1081/CLT-120030946 | s2cid = 39966201 }}</ref> In a double-blind, placebo-controlled trial of 326 people, 4 people had serious adverse events and 61% became resedated following the use of flumazenil.<ref>{{cite journal | title = Treatment of benzodiazepine overdose with flumazenil. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group | journal = Clinical Therapeutics | volume = 14 | issue = 6 | pages = 978–995 | year = 1992 | pmid = 1286503 }}</ref> Numerous contraindications to its use exist. It is contraindicated in people with a history of long-term use of benzodiazepines, those having ingested a substance that lowers the seizure threshold or may cause an [[Heart arrhythmia|arrhythmia]], and in those with abnormal vital signs.<ref>{{cite journal | vauthors = Spivey WH | title = Flumazenil and seizures: analysis of 43 cases | journal = Clinical Therapeutics | volume = 14 | issue = 2 | pages = 292–305 | year = 1992 | pmid = 1611650 }}</ref> One study found that only 10% of the people presenting with a [[benzodiazepine overdose]] are suitable candidates for treatment with flumazenil.<ref name="isbn0-07-136001-8">{{cite book |author=Goldfrank LR |title=Goldfrank's Toxicologic Emergencies |publisher=McGraw-Hill |year=2002 |isbn=978-0-07-136001-2 }}</ref>
<div class="skin-invert-image">
{{multiple image
 | align = center
 | width = 300
 | image1=US timeline. Benzodiazepine deaths.jpg | alt1=2
 | image2=US timeline. Opioid involvement in benzodiazepine overdose.jpg| alt2=2
 | image3=Flumazenil.svg| alt3=3
 | footer = Left: US yearly overdose deaths involving benzodiazepines.<ref name="NIDA-deaths">[http://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates Overdose Death Rates]. By [[National Institute on Drug Abuse]] (NIDA).</ref> Center: The top line represents the number of benzodiazepine deaths that also involved opioids in the US. The bottom line represents benzodiazepine deaths that did not involve [[opioid]]s.<ref name=NIDA-deaths/> Right: Chemical structure of the benzodiazepine [[flumazenil]], whose use is controversial following benzodiazepine overdose.
}}
</div>

==Interactions==
Individual benzodiazepines may have different [[drug interaction|interactions]] with certain drugs. Depending on their [[metabolism]] pathway, benzodiazepines can be divided roughly into two groups. The largest group consists of those that are metabolized by [[cytochrome P450]] (CYP450) enzymes and possess significant potential for interactions with other drugs. The other group comprises those that are metabolized through [[glucuronidation]], such as [[lorazepam]], [[oxazepam]], and [[temazepam]], and, in general, have few drug interactions.<ref name="isbn0-444-50998-4">{{cite book |veditors=Meyler L, Aronson JK |title=Meyler's Side Effects of Drugs: the International Encyclopedia of Adverse Drug Reactions and Interactions |edition=15th |publisher=Elsevier |year=2006 |pages=429–443 |isbn=978-0-444-50998-7 }}</ref>

Many drugs, including [[combined oral contraceptive pill|oral contraceptives]], some [[antibiotic]]s, [[antidepressant]]s, and [[Antifungal medication|antifungal]] agents, inhibit cytochrome enzymes in the liver. They reduce the rate of elimination of the benzodiazepines that are metabolized by CYP450, leading to possibly excessive drug accumulation and increased side-effects. In contrast, drugs that induce cytochrome P450 enzymes, such as [[Hypericum perforatum|St John's wort]], the antibiotic [[rifampicin]], and the [[anticonvulsants]] [[carbamazepine]] and [[phenytoin]], accelerate elimination of many benzodiazepines and decrease their action.<ref name="isbn1-58829-211-8"/><ref name="biadmtad">{{cite journal | vauthors = Norman TR, Ellen SR, Burrows GD | title = Benzodiazepines in anxiety disorders: managing therapeutics and dependence | journal = The Medical Journal of Australia | volume = 167 | issue = 9 | pages = 490–495 | year = 1997 | pmid = 9397065 | url = http://www.mja.com.au/public/mentalhealth/course/06norman.pdf | doi = 10.5694/j.1326-5377.1997.tb126684.x | s2cid = 35852993 | archive-date = 13 June 2001 | access-date = 11 December 2008 | archive-url = https://web.archive.org/web/20010613084333/http://www.mja.com.au/public/mentalhealth/course/06norman.pdf | url-status = dead }}</ref> Taking benzodiazepines with alcohol, [[opioid]]s and other [[depressant|central nervous system depressants]] potentiates their action. This often results in increased sedation, impaired motor coordination, suppressed breathing, and other adverse effects that have potential to be lethal.<ref name="isbn1-58829-211-8">{{cite book |author=Moody D |veditors=Raymon LP, Mozayani A |title=Handbook of Drug Interactions: a Clinical and Forensic Guide |publisher=Humana |year=2004 |pages=[https://archive.org/details/handbookofdrugin0000unse/page/3 3–88] |chapter=Drug interactions with benzodiazepines |isbn=978-1-58829-211-7 |chapter-url-access=registration |chapter-url=https://archive.org/details/handbookofdrugin0000unse |url=https://archive.org/details/handbookofdrugin0000unse/page/3 }}</ref><ref name=biadmtad/> [[Antacids]] can slow down absorption of some benzodiazepines; however, this effect is marginal and inconsistent.<ref name="isbn1-58829-211-8"/>

==Pharmacology==
===Pharmacodynamics===
[[Image:GABAA-receptor-protein-example-en.svg|thumb|class=skin-invert-image|alt=Figure of the GABA<sub>A</sub> receptor complex where the five subunits (two alpha, two beta, and one gamma) are symmetrically arranged in a pentagon shape about a central ion conduction pore. The location of the two GABA binding sites are located between the alpha and beta subunit, while the single benzodiazepine binding site is located between the alpha and gamma subunits.|Schematic diagram of the (α1)<sub>2</sub>(β2)<sub>2</sub>(γ2) GABA<sub>A</sub> receptor complex that depicts the five-protein subunits that form the receptor, the chloride (Cl<sup>−</sup>) ion channel pore at the center, the two GABA active binding sites at the α1 and β2 interfaces and the benzodiazepine (BZD) allosteric binding site at the α1 and γ2 interface.]]

Benzodiazepines work by increasing the effectiveness of the endogenous chemical, [[gamma-Aminobutyric acid|GABA]], to decrease the excitability of [[neuron]]s.<ref name="isbn0-12-088397-X">{{cite book |vauthors=Olsen RW, Betz H |veditors=Siegel GJ, Albers RW, Brady S, Price DD |title=Basic Neurochemistry: Molecular, Cellular and Medical Aspects |edition=7th |publisher=Elsevier |year=2006 |pages=291–302 |chapter=GABA and glycine |isbn=978-0-12-088397-4 }}</ref> This reduces the communication between neurons and, therefore, has a calming effect on many of the functions of the brain.

GABA controls the excitability of neurons by binding to the [[GABAA receptor|GABA<sub>A</sub> receptor]].<ref name="isbn0-12-088397-X"/> The GABA<sub>A</sub> receptor is a [[multiprotein complex|protein complex]] located in the [[chemical synapse|synapses]] between neurons. All GABA<sub>A</sub> receptors contain an [[ion channel]] that conducts [[chloride]] ions across neuronal [[cell membrane]]s and two binding sites for the [[neurotransmitter]] gamma-aminobutyric acid (GABA), while a subset of GABA<sub>A</sub> receptor complexes also contain a single binding site for benzodiazepines. Binding of benzodiazepines to this receptor complex does not alter binding of GABA. Unlike other positive [[allosteric modulator]]s that increase ligand binding, benzodiazepine binding acts as a positive allosteric modulator by increasing the total conduction of chloride ions across the neuronal cell membrane when GABA is already bound to its receptor. This increased chloride ion influx hyperpolarizes the neuron's [[membrane potential]]. As a result, the difference between resting potential and threshold potential is increased and [[action potential|firing]] is less likely.
Different GABA<sub>A</sub> receptor subtypes have varying distributions within different regions of the brain and, therefore, control distinct [[biological neural network|neuronal circuits]]. Hence, activation of different GABA<sub>A</sub> receptor subtypes by benzodiazepines may result in distinct pharmacological actions.<ref name="pmid16376150">{{cite journal | vauthors = Rudolph U, Möhler H | title = GABA-based therapeutic approaches: GABA<sub>A</sub> receptor subtype functions | journal = Current Opinion in Pharmacology | volume = 6 | issue = 1 | pages = 18–23 | date = February 2006 | pmid = 16376150 | doi = 10.1016/j.coph.2005.10.003 }}</ref> In terms of the mechanism of action of benzodiazepines, their similarities are too great to separate them into individual categories such as anxiolytic or hypnotic. For example, a hypnotic administered in low doses produces anxiety-relieving effects, whereas a benzodiazepine marketed as an anti-anxiety drug at higher doses induces sleep.<ref>{{cite book |vauthors=Puri BK, Tyrer P |title=Sciences Basic to Psychiatry |edition=2nd |year=1998 |publisher=Churchill Livingstone |isbn=978-0-443-05514-0 |pages=155–156 |chapter=Clinical psychopharmacology }}</ref>

The subset of GABA<sub>A</sub> receptors that also bind benzodiazepines are referred to as benzodiazepine receptors (BzR). The GABA<sub>A</sub> receptor is a [[heteromer]] composed of five subunits, the most common ones being two ''α''s, two ''β''s, and one ''γ'' (α<sub>2</sub>β<sub>2</sub>γ1). For each subunit, many subtypes exist (α<sub>1–6</sub>, β<sub>1–3</sub>, and γ<sub>1–3</sub>). GABA<sub>A</sub> receptors that are made up of different combinations of subunit subtypes have different properties, different distributions in the brain and different activities relative to pharmacological and clinical effects.<ref name="pmid8783370">{{cite journal | vauthors = Johnston GA | title = GABA<sub>A</sub> receptor pharmacology | journal = Pharmacology & Therapeutics | volume = 69 | issue = 3 | pages = 173–198 | year = 1996 | pmid = 8783370 | doi = 10.1016/0163-7258(95)02043-8 }}</ref> Benzodiazepines bind at the interface of the α and γ subunits on the GABA<sub>A</sub> receptor. Binding also requires that alpha subunits contain a [[histidine]] amino acid residue, (i.e., [[GABRA1|α<sub>1</sub>]], [[GABRA2|α<sub>2</sub>]], [[GABRA3|α<sub>3</sub>]], and [[GABRA5|α<sub>5</sub>]] containing GABA<sub>A</sub> receptors). For this reason, benzodiazepines show no affinity for GABA<sub>A</sub> receptors containing [[GABRA4|α<sub>4</sub>]] and [[GABRA6|α<sub>6</sub>]] subunits with an [[arginine]] instead of a histidine residue.<ref name="pmid15157182">{{cite journal | vauthors = Wafford KA, Macaulay AJ, Fradley R, O'Meara GF, Reynolds DS, Rosahl TW | title = Differentiating the role of gamma-aminobutyric acid type A (GABA<sub>A</sub>) receptor subtypes | journal = Biochemical Society Transactions | volume = 32 | issue = Pt3 | pages = 553–556 | date = June 2004 | pmid = 15157182 | doi = 10.1042/BST0320553 }}</ref> Once bound to the benzodiazepine receptor, the benzodiazepine [[ligand (biochemistry)|ligand]] locks the benzodiazepine receptor into a conformation in which it has a greater affinity for the [[gamma-aminobutyric acid|GABA]] [[neurotransmitter]]. This increases the frequency of the opening of the associated chloride [[ion channel]] and [[hyperpolarization (biology)|hyperpolarizes]] the membrane of the associated neuron. The inhibitory effect of the available GABA is potentiated, leading to sedative and anxiolytic effects. For instance, those ligands with high activity at the α<sub>1</sub> are associated with stronger [[hypnotic]] effects, whereas those with higher affinity for GABA<sub>A</sub> receptors containing α<sub>2</sub> and/or α<sub>3</sub> subunits have good anti-anxiety activity.<ref name="pmid9824848">{{cite journal | vauthors = Hevers W, Lüddens H | title = The diversity of GABA<sub>A</sub> receptors. Pharmacological and electrophysiological properties of GABA<sub>A</sub> channel subtypes | journal = Molecular Neurobiology | volume = 18 | issue = 1 | pages = 35–86 | date = August 1998 | pmid = 9824848 | doi = 10.1007/BF02741459 | s2cid = 32359279 }}</ref>

GABA<sub>A</sub> receptors participate in the regulation of synaptic pruning by prompting microglial spine engulfment.<ref>{{cite journal | vauthors = Afroz S, Parato J, Shen H, Smith SS | title = Synaptic pruning in the female hippocampus is triggered at puberty by extrasynaptic GABAA receptors on dendritic spines | journal = eLife | volume = 5 | pages = e15106 | date = May 2016 | pmid = 27136678 | pmc = 4871702 | doi = 10.7554/eLife.15106 | s2cid = 8422877 | title-link = doi | doi-access = free | veditors = Kennedy MB}}</ref> Benzodiazepines have been shown to upregulate microglial spine engulfment and prompt overzealous eradication of synaptic connections.<ref>{{cite journal | vauthors = Shi Y, Cui M, Ochs K, Brendel M, Strübing FL, Briel N, Eckenweber F, Zou C, Banati RB, Liu GJ, Middleton RJ, Rupprecht R, Rudolph U, Zeilhofer HU, Rammes G, Herms J, Dorostkar MM | title = Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO) | journal = Nature Neuroscience | volume = 25 | issue = 3 | pages = 317–329 | date = March 2022 | pmid = 35228700 | doi = 10.1038/s41593-022-01013-9 | s2cid = 247169270 }}</ref> This mechanism may help explain the increased risk of dementia associated with long-term benzodiazepine treatment.<ref>{{cite journal | vauthors = He Q, Chen X, Wu T, Li L, Fei X | title = Risk of Dementia in Long-Term Benzodiazepine Users: Evidence from a Meta-Analysis of Observational Studies | journal = Journal of Clinical Neurology | volume = 15 | issue = 1 | pages = 9–19 | date = January 2019 | pmid = 30375757 | pmc = 6325366 | doi = 10.3988/jcn.2019.15.1.9 }}</ref>

The benzodiazepine class of drugs also interact with [[translocator protein|peripheral benzodiazepine receptors]]. Peripheral benzodiazepine receptors are present in [[peripheral nervous system]] tissues, [[glial cells]], and to a lesser extent the central nervous system.<ref name="pmid12240908">{{cite journal | vauthors = Arvat E, Giordano R, Grottoli S, Ghigo E | title = Benzodiazepines and anterior pituitary function | journal = [[Journal of Endocrinological Investigation]] | volume = 25 | issue = 8 | pages = 735–747 | date = September 2002 | pmid = 12240908 | doi = 10.1007/bf03345110 | s2cid = 32002501 }}</ref> These peripheral receptors are not structurally related or coupled to GABA<sub>A</sub> receptors. They modulate the [[immune system]] and are involved in the body response to injury.<ref name="pmid9504140">{{cite journal | vauthors = Zavala F | title = Benzodiazepines, anxiety and immunity | journal = Pharmacology & Therapeutics | volume = 75 | issue = 3 | pages = 199–216 | date = September 1997 | pmid = 9504140 | doi = 10.1016/S0163-7258(97)00055-7 }}</ref><ref name="pmid9378234">{{cite journal | vauthors = Zisterer DM, Williams DC | title = Peripheral-type benzodiazepine receptors | journal = General Pharmacology | volume = 29 | issue = 3 | pages = 305–314 | date = September 1997 | pmid = 9378234 | doi = 10.1016/S0306-3623(96)00473-9 }}</ref> Benzodiazepines also function as weak [[adenosine reuptake inhibitor]]s. It has been suggested that some of their anticonvulsant, anxiolytic, and muscle relaxant effects may be in part mediated by this action.<ref name="pmid16780077">{{cite journal | vauthors = Narimatsu E, Niiya T, Kawamata M, Namiki A | title = [The mechanisms of depression by benzodiazepines, barbiturates and propofol of excitatory synaptic transmissions mediated by adenosine neuromodulation] | language = ja | journal = Masui | volume = 55 | issue = 6 | pages = 684–691 | date = June 2006 | pmid = 16780077 }}</ref> Benzodiazepines have binding sites in the periphery, however their effects on muscle tone is not mediated through these peripheral receptors. The peripheral binding sites for benzodiazepines are present in immune cells and gastrointestinal tract.<ref name="pmid18922233" />

===Pharmacokinetics===
{| class="wikitable sortable" style="float: right; margin-left:15px; text-align:center"
|-
! Benzodiazepine !! Half-life <br />([[prediction interval|range]], hours) !! Speed of onset
|-
| [[Alprazolam]]|| 6–15<ref name=OBrien>{{cite journal |vauthors=O'brien CP |title=Benzodiazepine use, abuse, and dependence |journal=The Journal of Clinical Psychiatry |volume=66 |issue=Suppl 2 |pages=28–33 |year=2005 |pmid=15762817 |url=https://www.psychiatrist.com/pcc/addiction/substance-use-disorders/benzodiazepine-abuse-dependence/ |access-date=5 September 2013}}</ref><ref>{{cite web|url=https://www.drugs.com/pro/alprazolam.html|title=Alprazolam – FDA prescribing information, side effects and uses|website=Drugs.com|access-date=28 August 2019}}</ref>|| Intermediate<ref name=OBrien />
|-
| [[Chlordiazepoxide]] || {{nts|10}}–30<ref name=OBrien /> || Intermediate<ref name=OBrien />
|-
| [[Clonazepam]] || {{nts|19}}–60<ref name=OBrien /> || Slow<ref name=OBrien />
|-
| [[Diazepam]] || {{nts|20}}–80<ref name=OBrien /> || Fast<ref name=OBrien />
|-
| [[Flunitrazepam]] || {{nts|18}}–26 || Fast
|-
| [[Lorazepam]] || {{nts|10}}–20<ref name=OBrien /> || Intermediate<ref name=OBrien />
|-
| [[Midazolam]] || {{nts|1.5}}–2.5<ref name=medsafe2012>{{cite web|url=http://www.medsafe.govt.nz/profs/datasheet/m/MidazolaminjPfizer.pdf|title=Midazolam Injection|website=[[Medsafe]]|publisher=New Zealand [[Ministry of Health (New Zealand)|Ministry of Health]]|access-date=6 April 2016|date=26 October 2012|url-status=dead|archive-url=https://web.archive.org/web/20160222123316/http://www.medsafe.govt.nz/profs/datasheet/m/MidazolaminjPfizer.pdf|archive-date=22 February 2016}}</ref> || Fast
|-
| [[Oxazepam]] || {{nts|5}}–10<ref name=OBrien /> || Slow<ref name=OBrien />
|-
| [[Prazepam]] || {{nts|50}}–200<ref name=OBrien /> || Slow<ref name=OBrien />
|-
| [[Triazolam]] || {{nts|1.5}} || Fast
|}
A benzodiazepine can be placed into one of three groups by its [[elimination half-life]], or time it takes for the body to eliminate half of the dose.<ref name="Cardinali_2006">{{cite book |veditors=Pandi-Perumal SR, Monti JM |vauthors=Cardinali DP, Monti JM |title=Clinical pharmacology of sleep |date=2006 |publisher=Birkhäuser |location=Basel |isbn=978-3-7643-7440-2 |pages=211–213 |chapter=Chronopharmacology and its implication to the pharmacology of sleep |chapter-url=https://books.google.com/books?id=nmG8Dyjzwu4C&q=benzodiazepines%20short%20intermediate%20long%20acting&pg=PA212}}</ref> Some benzodiazepines have long-acting [[active metabolites]], such as diazepam and chlordiazepoxide, which are metabolised into [[desmethyldiazepam]]. Desmethyldiazepam has a half-life of 36–200 hours, and flurazepam, with the main active metabolite of desalkylflurazepam, with a half-life of 40–250 hours. These long-acting metabolites are [[partial agonists]].<ref name=sddat>{{cite book |vauthors=Dikeos DG, Theleritis CG, Soldatos CR |chapter=Benzodiazepines: effects on sleep |pages=220–222 |title=Sleep Disorders: Diagnosis and Therapeutics |veditors=Pandi-Perumal SR, Verster JC, Monti JM, Lader M, Langer SZ |publisher=Informa Healthcare |year=2008 |isbn=978-0-415-43818-6}}</ref><ref name="manual" />
* Short-acting compounds have a median half-life of 1–12 hours. They have few residual effects if taken before bedtime, [[rebound insomnia]] may occur upon discontinuation, and they might cause daytime withdrawal symptoms such as next day [[rebound anxiety]] with prolonged usage. Examples are [[brotizolam]], [[midazolam]], and [[triazolam]].
* Intermediate-acting compounds have a median half-life of 12–40 hours. They may have some residual effects in the first half of the day if used as a [[hypnotic]]. Rebound insomnia, however, is more common upon discontinuation of intermediate-acting benzodiazepines than longer-acting benzodiazepines. Examples are [[alprazolam]], [[estazolam]], [[flunitrazepam]], [[clonazepam]], [[lormetazepam]], [[lorazepam]], [[nitrazepam]], and [[temazepam]].
* Long-acting compounds have a half-life of 40–250 hours. They have a risk of accumulation in the elderly and in individuals with severely impaired liver function, but they have a reduced severity of [[rebound effects]] and [[Drug withdrawal|withdrawal]]. Examples are [[diazepam]], [[clorazepate]], [[chlordiazepoxide]], and [[flurazepam]].

==Chemistry==
[[File:Benzodiazepine3.png|thumb|class=skin-invert-image|alt=On the left is the chemical structure of the parent benzodiazepine ring system, which consists of a seven-membered ring containing two nitrogen atoms fused to a six-membered ring. The two nitrogen atoms are labeled one and four. On the right is the chemical structure of a pharmacologically active benzodiazepine in which alkyl, phenyl, and halogen groups attach to the one, five, and seven positions, respectively, and the carbon atom at position two is double-bonded to an exocyclic oxygen atom. The ortho and para positions of the phenyl substituent are labeled two-prime and 4-prime, respectively.|'''Left''': The 1,4-benzodiazepine ring system. '''Right''': 5-phenyl-1''H''-benzo[''e''] [1,4]diazepin-2(3''H'')-one forms the skeleton of many of the most common benzodiazepine pharmaceuticals, such as [[diazepam]] (7-chloro-1-methyl substituted).]]
[[File:Bzr pm.png|thumb|class=skin-invert-image|alt=Superposition of the chemical structures of a benzodiazepine and nonbenzodiazepine ligand and their interactions with binding sites within the receptor.|A [[pharmacophore]] model of the benzodiazepine binding site on the GABA<sub>A</sub> receptor.<ref name="isbn0-471-21384-5"/> White sticks represent the carbon atoms of the benzodiazepine [[diazepam]], while green represents carbon atoms of the nonbenzodiazepine [[CGS-9896]]. Red and blue sticks are oxygen and nitrogen atoms that are present in both structures. The red spheres labeled H1 and H2/A3 are, respectively, [[hydrogen bond]] donating and accepting sites in the receptor, while L1, L2, and L3 denote [[lipophilicity|lipophilic]] binding sites.]]
Benzodiazepines share a similar chemical structure, and their effects in humans are mainly produced by the [[allosteric]] modification of a specific kind of [[neurotransmitter receptor]], the [[GABAA receptor|GABA<sub>A</sub> receptor]], which increases the overall conductance of these inhibitory channels; this results in the various therapeutic effects as well as adverse effects of benzodiazepines.<ref name="isbn0-12-088397-X"/> Other less important [[mode of action|modes of action]] are also known.<ref name="pmid9504140"/><ref name="pmid16780077"/>

The term ''benzodiazepine'' is the [[IUPAC nomenclature|chemical name]] for the [[heterocycle|heterocyclic]] ring system (see figure to the right), which is a fusion between the [[benzene]] and [[diazepine]] ring systems.<ref name=IUPAC>{{BlueBook1993 |pages=40–43 }}; {{cite journal |publisher=Moss GP |year=1998 |title=Nomenclature of fused and bridged fused ring systems (IUPAC Recommendations 1998) |url=http://media.iupac.org/publications/pac/1998/pdf/7001x0143.pdf |archive-url=https://ghostarchive.org/archive/20221009/http://media.iupac.org/publications/pac/1998/pdf/7001x0143.pdf |archive-date=9 October 2022 |url-status=live |journal=Pure and Applied Chemistry |volume=70 |issue=1 |pages=143–216 |doi=10.1351/pac199870010143 |s2cid=5776706 | vauthors = Moss GP }}</ref> Under [[Hantzsch–Widman nomenclature]], a [[diazepine]] is a heterocycle with two [[nitrogen]] atoms, five [[carbon]] atom and the maximum possible number of cumulative [[double bond]]s. The "benzo" prefix indicates the [[benzene]] ring fused onto the diazepine ring.<ref name="IUPAC" />

Benzodiazepine drugs are substituted 1,4-benzodiazepines, although the chemical term can refer to many other compounds that do not have useful pharmacological properties. Different benzodiazepine drugs have different side groups attached to this central structure. The different side groups affect the binding of the molecule to the GABA<sub>A</sub> receptor and so modulate the pharmacological properties.<ref name="isbn0-12-088397-X"/> Many of the pharmacologically active "classical" benzodiazepine drugs contain the 5-phenyl-1''H''-benzo[''e''] [1,4]diazepin-2(3''H'')-one substructure (see figure to the right).<ref name=CAS>[[CAS registry number]]:{{CAS|2898-08-0|1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one}}; other names: Ro 05-2921, dechlorodemethyldiazepam.</ref> Benzodiazepines have been found to mimic protein reverse turns structurally, which enable them with their biological activity in many cases.<ref>{{cite journal |vauthors=Ripka WC, De Lucca GV, Bach AC, Pottorf RS, Blaney JM | title = Protein β-turn mimetics I. Design, synthesis, and evaluation in model cyclic peptides | journal = Tetrahedron | volume = 49 | issue = 17 | pages = 3593–3608 | year = 1993 | doi = 10.1016/S0040-4020(01)90217-0 }}</ref><ref>{{cite journal |vauthors=Hata M, Marshall GR | title = Do benzodiazepines mimic reverse-turn structures? | journal = Journal of Computer-Aided Molecular Design | volume = 20 | issue = 5 | pages = 321–331 | year = 2006 | pmid = 16972167 | doi = 10.1007/s10822-006-9059-x | bibcode = 2006JCAMD..20..321H | s2cid = 2777635 }}</ref>

[[Nonbenzodiazepine]]s also bind to the benzodiazepine binding site on the GABA<sub>A</sub> receptor and possess similar pharmacological properties. While the nonbenzodiazepines are by definition structurally unrelated to the benzodiazepines, both classes of drugs possess a common [[pharmacophore]] (see figure to the lower-right), which explains their binding to a common receptor site.<ref name="isbn0-471-21384-5">{{cite book |vauthors=Madsen U, Bräuner-Osborne H, Greenwood JR, Johansen TN, Krogsgaard-Larsen P, Liljefors T, Nielsen M, Frølund B |editor=Gad SC |title=Drug Discovery Handbook |publisher=Wiley-Interscience/J. Wiley |location=Hoboken, N.J |year=2005 |pages=797–907 |chapter=GABA and Glutamate receptor ligands and their therapeutic potential in CNS disorders |isbn=978-0-471-21384-0 }}</ref>

Not all benzodiazepines increase the conductance of the GABA<sub>A</sub> receptor. [[Flumazenil]], an imidazobenzodiazepine, is an antidote for some benzodiazepine overdoses.<ref>{{cite journal | vauthors = Hood SD, Norman A, Hince DA, Melichar JK, Hulse GK | title = Benzodiazepine dependence and its treatment with low dose flumazenil | journal = British Journal of Clinical Pharmacology | volume = 77 | issue = 2 | pages = 285–294 | date = February 2014 | pmid = 23126253 | pmc = 4014019 | doi = 10.1111/bcp.12023 }}</ref> The structual scaffold can even be used to target receptors other than GABA<sub>A</sub>.<ref>{{cite journal | vauthors = Mian MY, Sharmin D, Mondal P, Belayet JB, Hossain MM, McCusker P, Ryan KT, Fedorov AY, Green HA, Ericksen SS, Zamanian M, Tiruveedhula VV, Cook JM, Chan JD | title = Development of non-sedating benzodiazepines with ''in vivo'' antischistosomal activity | journal = Antimicrobial Agents and Chemotherapy | volume = 68 | issue = 9 | pages = e0036924 | date = September 2024 | pmid = 39136467 | doi = 10.1128/aac.00369-24 | pmc = 11373208 }}</ref>

===Types===
* 2-keto compounds:
::[[clorazepate]], [[diazepam]], [[flurazepam]], [[halazepam]], [[prazepam]], and others<ref name=ub>{{cite web| vauthors = Juergens SM |title=Understanding Benzodiazepines|url=http://www.csam-asam.org/sites/default/files/pdf/misc/Juergens.pdf|publisher=California Society of Addiction Medicine|access-date=25 April 2012|archive-url=https://web.archive.org/web/20120508050910/http://www.csam-asam.org/sites/default/files/pdf/misc/Juergens.pdf|archive-date=8 May 2012|url-status=dead}}</ref><ref name=PC89>{{cite journal |vauthors=Carlo P, Finollo R, Ledda A, Brambilla G | title = Absence of liver DNA fragmentation in rats treated with high oral doses of 32 benzodiazepine drugs | journal = Fundamental and Applied Toxicology | volume = 12 | issue = 1 | pages = 34–41 | date = January 1989 | pmid = 2925017 | doi = 10.1016/0272-0590(89)90059-6 }}</ref>
* 3-hydroxy compounds:
::[[lorazepam]], [[lormetazepam]], [[oxazepam]], [[temazepam]]<ref name=ub/><ref name=PC89/>
* 7-nitro compounds:
::[[clonazepam]], [[flunitrazepam]], [[nimetazepam]], [[nitrazepam]]<ref name=ub/><ref name=PC89/>
* Triazolo compounds:
::[[adinazolam]], [[alprazolam]], [[estazolam]], [[triazolam]]<ref name=ub/><ref name=PC89/>
* Imidazo compounds:
::[[climazolam]], [[loprazolam]], [[midazolam]]<ref name=ub/><ref name=PC89/>
* 1,5-benzodiazepines:
::[[clobazam]]

==History==
[[File:Chlordiazepoxide structure.svg|thumb|class=skin-invert-image|alt=Chemical structure diagram of a benzene ring fused to a diazepine ring. Cl is attached to the benzene; N, H, CH3, and O are attached to the diazepine.|The molecular structure of [[chlordiazepoxide]], the first benzodiazepine, marketed by [[Hoffmann–La Roche]] beginning in 1960 and branded as Librium]]
The first benzodiazepine, [[chlordiazepoxide]] (''Librium''), was synthesized in 1955 by [[Leo Sternbach]] while working at [[Hoffmann–La Roche]] on the development of tranquilizers. The pharmacological properties of the compounds prepared initially were disappointing, and Sternbach abandoned the project. Two years later, in April 1957, co-worker Earl Reeder noticed a "nicely crystalline" compound left over from the discontinued project while spring-cleaning in the lab. This compound, later named chlordiazepoxide, had not been tested in 1955 because of Sternbach's focus on other issues. Expecting pharmacology results to be negative, and hoping to publish the chemistry-related findings, researchers submitted it for a standard battery of animal tests. The compound showed very strong [[sedative]], [[anticonvulsant]], and [[muscle relaxant]] effects. These impressive clinical findings led to its speedy introduction throughout the world in 1960 under the brand name ''Librium''.<ref name="pmid34039">{{cite journal | author = Sternbach LH | title = The benzodiazepine story | journal = Journal of Medicinal Chemistry | volume = 22 | issue = 1 | pages = 1–7 | year = 1979 | pmid = 34039 | doi = 10.1021/jm00187a001 | quote = During this cleanup operation, my co-worker, Earl Reeder, drew my attention to a few hundred milligrams of two products, a nicely crystalline base and its hydrochloride. Both the base, which had been prepared by treating the quinazoline N-oxide 11 with methylamine, and its hydrochloride had been made sometime in 1955. The products were not submitted for pharmacological testing at that time because of our involvement with other problems }}</ref><ref name="Miller-Gold">{{cite journal |vauthors=Miller NS, Gold MS | title = Benzodiazepines: reconsidered | journal = Advances in Alcohol & Substance Abuse | volume = 8 | issue = 3–4 | pages = 67–84 | year = 1990 | pmid = 1971487 | doi = 10.1300/J251v08n03_06 }}</ref> Following chlordiazepoxide, [[diazepam]] marketed by Hoffmann–La Roche under the brand name ''Valium'' in 1963, and for a while the two were the most commercially successful drugs. The introduction of benzodiazepines led to a decrease in the prescription of [[barbiturate]]s, and by the 1970s they had largely replaced the older drugs for sedative and [[hypnotic]] uses.<ref name="isbn0-19-517668-5">{{cite book |author=Shorter E |title=A Historical Dictionary of Psychiatry |publisher=Oxford University Press |year=2005 |chapter=Benzodiazepines |pages=41–42 |isbn=978-0-19-517668-1 }}</ref>

The new group of drugs was initially greeted with optimism by the medical profession, but gradually concerns arose; in particular, the risk of dependence became evident in the 1980s. Benzodiazepines have a unique history in that they were responsible for the largest-ever [[class-action lawsuit]] against [[drugs manufacturers|drug manufacturers]] in the United Kingdom, involving 14,000 patients and 1,800 [[law firms]] that alleged the manufacturers knew of the dependence potential but intentionally withheld this information from doctors. At the same time, 117 general practitioners and 50 health authorities were sued by patients to recover damages for the harmful effects of [[benzodiazepine dependence|dependence]] and [[Drug withdrawal|withdrawal]]. This led some doctors to require a signed consent form from their patients and to recommend that all patients be adequately warned of the risks of dependence and withdrawal before starting treatment with benzodiazepines.<ref>{{cite journal | vauthors = King MB | title = Is there still a role for benzodiazepines in general practice? | journal = The British Journal of General Practice | volume = 42 | issue = 358 | pages = 202–205 | date = May 1992 | pmid = 1389432 | pmc = 1372025 }}</ref> The court case against the drug manufacturers never reached a verdict; [[legal aid]] had been withdrawn and there were allegations that the consultant psychiatrists, the expert witnesses, had a conflict of interest.<ref name="urlHouse of Commons">{{cite web |url=https://publications.parliament.uk/pa/cm199899/cmselect/cmhealth/549/99072723.htm |title=Memorandum by Dr Reg Peart |author=Peart R |date=1 June 1999 |website=Minutes of Evidence |publisher=Select Committee on Health, House of Commons, UK Parliament |access-date=27 May 2009 }}</ref><ref name=":1">{{cite journal|date=23 January 1993|title=News|journal=BMJ: British Medical Journal|volume=306|issue=6872|pages=227–232|doi=10.1136/bmj.306.6872.227|issn=0959-8138|pmc=1676757}}</ref> The court case fell through, at a cost of £30 million, and led to more cautious funding through legal aid for future cases.<ref>{{cite journal | vauthors = Richards T | title = End to insurers using genetic data urged | journal = BMJ | volume = 313 | issue = 7061 | pages = 838 | date = October 1996 | pmid = 8870565 | pmc = 2359076 | doi = 10.1136/bmj.313.7061.838a }}</ref> This made future class action lawsuits less likely to succeed, due to the high cost from financing a smaller number of cases, and increasing charges for losing the case for each person involved.<ref name=":1" />

Although antidepressants with anxiolytic properties have been introduced, and there is increasing awareness of the adverse effects of benzodiazepines, prescriptions for short-term anxiety relief have not significantly dropped.<ref name=pmid18671662>{{cite journal | author = Lader M | title = Effectiveness of benzodiazepines: do they work or not? | journal = Expert Review of Neurotherapeutics | volume = 8 | issue = 8 | pages = 1189–1191 | year = 2008 | pmid = 18671662 | doi = 10.1586/14737175.8.8.1189 | s2cid = 45155299 | type = PDF }}</ref> For treatment of insomnia, benzodiazepines are now less popular than [[nonbenzodiazepine]]s, which include [[zolpidem]], [[zaleplon]] and [[eszopiclone]].<ref>{{cite journal | author = Jufe GS | title = [New hypnotics: perspectives from sleep physiology] | journal = Vertex | volume = 18 | issue = 74 | pages = 294–299 | date = Jul–Aug 2007 | pmid = 18265473 }}</ref> Nonbenzodiazepines are molecularly distinct, but nonetheless, they work on the same benzodiazepine receptors and produce similar sedative effects.<ref name=wake>{{cite journal | author = Lemmer B | title = The sleep–wake cycle and sleeping pills | journal = Physiology & Behavior | volume = 90 | issue = 2–3 | pages = 285–293 | year = 2007 | pmid = 17049955 | doi = 10.1016/j.physbeh.2006.09.006 | s2cid = 43180871 }}</ref>

Benzodiazepines have been detected in plant specimens and brain samples of animals not exposed to synthetic sources, including a human brain from the 1940s. However, it is unclear whether these compounds are biosynthesized by microbes or by plants and animals themselves. A microbial biosynthetic pathway has been proposed.<ref>{{cite journal | vauthors = Sand P, Kavvadias D, Feineis D, Riederer P, Schreier P, Kleinschnitz M, Czygan FC, Abou-Mandour A, Bringmann G, Beckmann H | title = Naturally occurring benzodiazepines: current status of research and clinical implications | journal = European Archives of Psychiatry and Clinical Neuroscience | volume = 250 | issue = 4 | pages = 194–202 | date = 1 August 2000 | pmid = 11009072 | doi = 10.1007/s004060070024 | s2cid = 1125401 }}</ref>

== Society and culture ==
===Legal status===
In the [[United States]], benzodiazepines are [[Controlled Substances Act#Schedule IV drugs|Schedule IV drugs]] under the Federal [[Controlled Substances Act]], even when not on the market (for example, [[flunitrazepam]]<ref name="deaRohypnol">{{cite web|url=https://www.dea.gov/factsheets/rohypnol|title=Rohypnol|publisher=[[Drug Enforcement Administration]]|access-date=2024-09-18}}</ref>), with the exception of [[flualprazolam]], [[etizolam]], [[clonazolam]], [[flubromazolam]], and [[diclazepam]] which are placed in [[Controlled Substances Act#Schedule I drugs|Schedule I]].<ref name="deaDiversion">{{cite web|url=https://www.deadiversion.usdoj.gov/drug_chem_info/benzo.pdf|title=BENZODIAZEPINES|publisher=[[Drug Enforcement Administration]]|access-date=2024-09-18}}</ref>

In Canada, possession of benzodiazepines is legal for personal use. All benzodiazepines are categorized as [[Controlled Drugs and Substances Act#Schedule IV|Schedule IV]] substances under the [[Controlled Drugs and Substances Act]].<ref name="urlControlled Drugs and Substances Act">{{cite web | url = http://laws-lois.justice.gc.ca/eng/acts/C-38.8/ | title = Controlled Drugs and Substances Act | publisher = Canadian Department of Justice | access-date = 27 May 2009 }}</ref>

In the United Kingdom, benzodiazepines are Class C controlled drugs, carrying the maximum penalty of 7 years imprisonment, an unlimited fine or both for possession and a maximum penalty of 14 years imprisonment, an unlimited fine or both for supplying benzodiazepines to others.<ref name="urlwww.blackpool.nhs.uk">{{cite web | url = http://www.blackpool.nhs.uk/images/uploads/CD-update-GP-v2-may08.pdf | title = Medicines Management Update | author = Blackpool NHS Primary Care Trust | date = 1 May 2008 | publisher = United Kingdom [[National Health Service]] | access-date = 27 May 2009 | url-status=dead | archive-url = https://web.archive.org/web/20101204070730/http://www.blackpool.nhs.uk/images/uploads/CD-update-GP-v2-may08.pdf | archive-date = 4 December 2010 }}</ref><ref>{{cite web | url = http://www.homeoffice.gov.uk/documents/cdlist.pdf?view=Binary | title = List of Drugs Currently Controlled Under The Misuse of Drugs Legislation | access-date = 27 May 2009 | publisher = British Government | website = Misuse of Drugs Act UK | url-status=dead | archive-url = https://web.archive.org/web/20070205105239/http://www.homeoffice.gov.uk/documents/cdlist.pdf?view=Binary | archive-date = 5 February 2007 }}</ref>

In the Netherlands, since October 1993, benzodiazepines, including formulations containing less than 20&nbsp;mg of temazepam, are all placed on List 2 of the [[Opium Law]]. A prescription is needed for possession of all benzodiazepines. Temazepam formulations containing 20&nbsp;mg or greater of the drug are placed on List 1, thus requiring doctors to write prescriptions in the List 1 format.<ref name="urlwww.cannabisbureau.nl">{{cite web|url=http://www.cannabisbureau.nl/pdf/Opiumwet_EN_29nov2004.pdf |title=Opium Law |date=29 November 2004 |publisher=Dutch Government |access-date=27 May 2009 |url-status=dead |archive-url=https://web.archive.org/web/20081020220115/http://www.cannabisbureau.nl/pdf/Opiumwet_EN_29nov2004.pdf |archive-date=20 October 2008 }}</ref>

In East Asia and Southeast Asia, [[temazepam]] and [[nimetazepam]] are often heavily controlled and restricted. In certain countries, [[triazolam]], [[flunitrazepam]], [[flutoprazepam]] and [[midazolam]] are also restricted or controlled to certain degrees. In Hong Kong, all benzodiazepines are regulated under Schedule 1 of [[Hong Kong|Hong Kong's]] Chapter 134 ''Dangerous Drugs Ordinance''.<ref>{{cite web | author = Hong Kong Government | author-link = Hong Kong Government | website = Hong Kong Ordinances | title = Dangerous Drugs Ordinance&nbsp;– Schedule 1 | url = http://www.hklii.org/hk/legis/en/ord/134/sch1.html | publisher = hklii.org | location = Hong Kong | access-date = 10 December 2015 | archive-date = 27 September 2011 | archive-url = https://web.archive.org/web/20110927233610/http://www.hklii.org/hk/legis/en/ord/134/sch1.html | url-status = dead }}</ref> Previously only [[brotizolam]], [[flunitrazepam]] and [[triazolam]] were classed as dangerous drugs.<ref>{{cite journal | vauthors = Lee KK, Chan TY, Chan AW, Lau GS, Critchley JA | title = Use and abuse of benzodiazepines in Hong Kong 1990–1993 – the impact of regulatory changes | journal = Journal of Toxicology: Clinical Toxicology | volume = 33 | issue = 6 | pages = 597–602 | year = 1995 | pmid = 8523479 | doi = 10.3109/15563659509010615 }}</ref>

Internationally, benzodiazepines are categorized as [[Convention on Psychotropic Substances#Schedules of Controlled Substances|Schedule IV]] controlled drugs, apart from flunitrazepam, which is a [[Convention on Psychotropic Substances#Schedules of Controlled Substances|Schedule III]] drug under the [[Convention on Psychotropic Substances]].<ref>{{cite web|url=http://www.incb.org/pdf/e/list/green.pdf |title=List of psychotropic substances under international control |access-date=17 December 2008 |publisher=International Narcotics Control Board |author-link=International Narcotics Control Board |date=August 2003 |website=incb.org |url-status=dead |archive-url=https://web.archive.org/web/20051205125434/http://www.incb.org/pdf/e/list/green.pdf |archive-date=5 December 2005 }}</ref>

===Recreational use===
{{Main|Benzodiazepine drug misuse|Drug-related crime}}
[[File:Xanax 2 mg.jpg|thumb|Xanax ([[alprazolam]]) 2 mg tri-score tablets]]
Benzodiazepines are considered major addictive substances.<ref name=pmid10622686>{{cite journal | author = Lader MH | title = Limitations on the use of benzodiazepines in anxiety and insomnia: are they justified? | journal = European Neuropsychopharmacology | volume = 9 | issue = Suppl 6 | pages = S399–405 | year = 1999 | pmid = 10622686 | doi = 10.1016/S0924-977X(99)00051-6 | s2cid = 43443180 }}</ref> Non-medical benzodiazepine use is mostly limited to individuals who use other substances, i.e., people who engage in polysubstance use.<ref>{{cite web |url=http://www.exchangesupplies.org/conferences/NDTC/2009_NDTC/speakers/chris_ford.html |title=What is possible with benzodiazepines |author=Chris Ford |year=2009 |publisher=Exchange Supplies, 2009 National Drug Treatment Conference |location=UK|archive-url=https://web.archive.org/web/20100501121221/http://www.exchangesupplies.org/conferences/NDTC/2009_NDTC/speakers/chris_ford.html |archive-date=1 May 2010 |url-status=dead }}</ref> On the international scene, [[Benzodiazepine drug misuse#Legal status|benzodiazepines are categorized]] as [[Convention on Psychotropic Substances#Schedules of Controlled Substances|Schedule IV]] controlled drugs by the [[INCB]], apart from [[flunitrazepam]], which is a [[Convention on Psychotropic Substances#Schedules of Controlled Substances|Schedule III]] drug under the [[Convention on Psychotropic Substances]].<ref>{{cite web|url=http://www.incb.org/pdf/e/list/green.pdf |title=List of psychotropic substances under international control |access-date=17 December 2008 |publisher=International Narcotics Control Board |year=2003 |url-status=dead |archive-url=https://web.archive.org/web/20051205125434/http://www.incb.org/pdf/e/list/green.pdf |archive-date=5 December 2005 |author-link=International Narcotics Control Board }}</ref> Some variation in drug scheduling exists in individual countries; for example, in the United Kingdom, [[midazolam]] and [[temazepam]] are [[Controlled Drug#Schedule 3 - CD No Reg|Schedule III controlled drugs]].<ref>{{cite web |url= https://bnf.nice.org.uk/guidance/controlled-drugs-and-drug-dependence.html |title=Controlled drugs and drug dependence |author-link=National Institute for Clinical Excellence |date=3 January 2020 |publisher=British National Formulary |location=United Kingdom }}(Note: The ''[[British National Formulary]]'' is only accessible in the UK. A [https://bnf.nice.org.uk/medicines-guidance/controlled-drugs-and-drug-dependence/ cached copy] is available from Google.)</ref>

British law requires that temazepam (but ''not'' midazolam) be stored in safe custody. Safe custody requirements ensures that pharmacists and doctors holding stock of temazepam must store it in securely fixed double-locked steel safety cabinets and maintain a written register, which must be bound and contain separate entries for temazepam and must be written in ink with no use of correction fluid (although a written register is not required for temazepam in the United Kingdom). Disposal of expired stock must be witnessed by a designated inspector (either a local drug-enforcement police officer or official from health authority).<ref>Home Office (2005). [http://www.homeoffice.gov.uk/about-us/home-office-circulars/circulars-2005/048-2005/ Explanatory memorandum to the misuse of drugs and the misuse of drugs] {{webarchive |url=https://web.archive.org/web/20101216234732/http://www.homeoffice.gov.uk/about-us/home-office-circulars/circulars-2005/048-2005/ |date=16 December 2010 }} (supply to addicts) (amendment) regulations 2005. No. 2864. Accessed 20–10–03</ref><ref>{{cite web |url=http://www.homeoffice.gov.uk/publications/drugs/drug-licences/controlled-drugs-list?view=Binary |format=PDF |title=List of drugs currently controlled under the misuse of drugs legislation |date=25 October 2010 |access-date=30 January 2011 |publisher=UK Government Home Office |archive-url=https://web.archive.org/web/20110218033313/http://www.homeoffice.gov.uk/publications/drugs/drug-licences/controlled-drugs-list?view=Binary |archive-date=18 February 2011 |url-status=dead }}</ref> Benzodiazepine use ranges from occasional binges on large doses, to chronic and compulsive drug use of high doses.<ref>{{cite book | vauthors = Karch SB |title=Drug Abuse Handbook |url=https://books.google.com/books?id=F0mUte90ATUC |edition=2nd |year= 2006 |publisher=CRC Press |location=US |isbn=978-0-8493-1690-6 |page=217 }}</ref>

Benzodiazepines are commonly used recreationally by poly-drug users. [[Death|Mortality]] is higher among [[Poly drug use|poly-drug users]] that also use benzodiazepines. Heavy alcohol use also increases [[Mortality rate|mortality]] among poly-drug users.<ref name="Charlson_2009">{{cite journal |vauthors=Charlson F, Degenhardt L, McLaren J, Hall W, Lynskey M | title = A systematic review of research examining benzodiazepine-related mortality | journal = Pharmacoepidemiology and Drug Safety | volume = 18 | issue = 2 | pages = 93–103 | year = 2009 | pmid = 19125401 | doi = 10.1002/pds.1694 | s2cid = 20125264 }}</ref> Polydrug use involving benzodiazepines and alcohol can result in an increased risk of blackouts, risk-taking behaviours, seizures, and overdose.<ref>{{cite journal | vauthors = Bright J, Martin AJ, Richards M, Morie M |date=16 December 2022 |title=The Benzo Research Project: An evaluation of recreational benzodiazepine use amongst UK young people (18-25) |url=https://zenodo.org/record/7813470 |journal=Zenodo |doi=10.5281/zenodo.7813470}}</ref> Dependence and tolerance, often coupled with dosage escalation, to benzodiazepines can develop rapidly among people who misuse drugs; withdrawal syndrome may appear after as little as three weeks of continuous use. Long-term use has the potential to cause both physical and psychological dependence and severe withdrawal symptoms such as depression, anxiety (often to the point of [[panic attack]]s), and [[agoraphobia]].<ref name=ohop>{{cite book |vauthors=McIntosh A, Semple D, Smyth R, Burns J, Darjee R |title=Oxford Handbook of Psychiatry |edition=1st |publisher=Oxford University Press |year=2005 |page=540 |chapter=Depressants |isbn=978-0-19-852783-1 }}</ref> Benzodiazepines and, in particular, [[temazepam]] are sometimes used intravenously, which, if done incorrectly or in an unsterile manner, can lead to medical complications including [[abscess]]es, [[cellulitis]], [[thrombophlebitis]], arterial puncture, [[deep vein thrombosis]], and [[gangrene]]. Sharing syringes and needles for this purpose also brings up the possibility of transmission of [[hepatitis]], HIV, and other diseases. Benzodiazepines are also misused [[intranasally]], which may have additional health consequences. Once benzodiazepine dependence has been established, a clinician usually converts the patient to an equivalent dose of diazepam before beginning a gradual reduction program.<ref name="pmid9274553">{{cite journal |vauthors=Gerada C, Ashworth M | title = ABC of mental health. Addiction and dependence – I: Illicit drugs | journal = [[BMJ]] | volume = 315 | issue = 7103 | pages = 297–300 | year = 1997 | pmid = 9274553 | pmc = 2127199 | doi = 10.1136/bmj.315.7103.297 }}</ref>

A 1999–2005 Australian police survey of detainees reported preliminary findings that self-reported users of benzodiazepines were less likely than non-user detainees to work full-time and more likely to receive government benefits, use methamphetamine or heroin, and be arrested or imprisoned.<ref>{{cite journal |url=http://aic.gov.au/media_library/publications/tandi_pdf/tandi336.pdf |title=Benzodiazepine use and harms among police detainees in Australia |publisher=Loxley W |year=2007 |issn=0817-8542 |journal=Trends & Issues in Crime and Criminal Justice |issue=336 |access-date=10 June 2009 |archive-url=https://web.archive.org/web/20170812072936/http://www.aic.gov.au/media_library/publications/tandi_pdf/tandi336.pdf |archive-date=12 August 2017 |url-status=dead }}</ref> Benzodiazepines are sometimes used for criminal purposes; they serve to incapacitate a victim in cases of [[drug assisted rape]] or robbery.<ref>{{cite journal | author = Kintz P | title = Bioanalytical procedures for detection of chemical agents in hair in the case of drug-facilitated crimes | journal = Analytical and Bioanalytical Chemistry | volume = 388 | issue = 7 | pages = 1467–1474 | year = 2007 | pmid = 17340077 | doi = 10.1007/s00216-007-1209-z | s2cid = 28981255 }}</ref>

Overall, [[anecdotal evidence]] suggests that [[temazepam]] may be the most psychologically [[Substance dependence|habit-forming (addictive)]] benzodiazepine. Non-medical temazepam use reached epidemic proportions in some parts of the world, in particular, in Europe and Australia, and is a major addictive substance in many Southeast Asian countries. This led authorities of various countries to place temazepam under a more restrictive legal status. Some countries, such as Sweden, banned the drug outright.<ref>{{cite web|url=http://www.benzo.org.uk/ashbzab.htm |title=Benzodiazepine abuse |publisher=Benzo.org.uk |access-date=28 November 2011}}</ref> Temazepam also has certain pharmacokinetic properties of absorption, distribution, elimination, and clearance that make it more apt to non-medical use compared to many other benzodiazepines.<ref name="pmid1786493">{{cite journal |vauthors=Farré M, Camí J | title = Pharmacokinetic considerations in abuse liability evaluation | journal = British Journal of Addiction | volume = 86 | issue = 12 | pages = 1601–1606 | date = December 1991 | pmid = 1786493 | doi = 10.1111/j.1360-0443.1991.tb01754.x }}</ref><ref>{{cite journal |vauthors=Busto U, Sellers EM | title = Pharmacokinetic determinants of drug abuse and dependence. A conceptual perspective | journal =Clinical Pharmacokinetics | volume = 11 | issue = 2 | pages = 144–153 | year = 1986 | pmid = 3514044 | doi = 10.2165/00003088-198611020-00004 | s2cid = 41959044 }}</ref>

==Veterinary use==
Benzodiazepines are used in [[veterinary]] practice in the treatment of various disorders and conditions. As in humans, they are used in the first-line management of [[seizures]], [[status epilepticus]], and [[tetanus]], and as maintenance therapy in epilepsy (in particular, in cats).<ref name = MVM>{{cite book |veditors=Kahn CM, Line S, Aiello SE |title=The Merck Veterinary Manual|year=2005 |publisher=Wiley |edition=9th |isbn=978-0-911910-50-6 |title-link=Merck Veterinary Manual}}</ref><ref>{{cite journal | author = Frey HH | title = Anticonvulsant drugs used in the treatment of epilepsy | journal = Problems in Veterinary Medicine | volume = 1 | issue = 4 | pages = 558–577 | year = 1989 | pmid = 2520134 }}</ref><ref>{{cite journal | author = Podell M | title = Seizures in dogs | journal = Veterinary Clinics of North America: Small Animal Practice | volume = 26 | issue = 4 | pages = 779–809 | year = 1996 | pmid = 8813750 | doi = 10.1016/S0195-5616(96)50105-1 }}</ref> They are widely used in small and large animals (including horses, swine, cattle and exotic and wild animals) for their anxiolytic and sedative effects, as pre-medication before surgery, for induction of [[anesthesia]] and as adjuncts to anesthesia.<ref name = MVM/><ref name=Adams>{{cite book |author=Gross ME |chapter=Tranquilizers, α<sub>2</sub>-adrenergic agonists, and related agents |editor=Adams RH |title=Veterinary Pharmacology and Therapeutics |edition=8th |publisher=Iowa State University Press |year=2001 |pages=325–333 |isbn=978-0-8138-1743-9 }}</ref>

==References==
{{Reflist}}

==External links==
* {{cite book |url=https://benzo.org.uk/manual/|title=Benzodiazepines: how they work & how to withdraw (aka The Ashton Manual) |author=Ashton CH |year=2002 }}
* {{cite web |url=https://benzo.org.uk/bzequiv.htm |title=Benzodiazepine equivalence table |author=Ashton CH |year=2007 }}
* {{cite web |url=https://www.inchem.org/documents/pims/pharm/pimg008.htm |title=Benzodiazepines |author=Fruchtengarten L |date=April 1998 |website=Poisons Information Monograph (Group monograph) G008 |publisher=[[International Programme on Chemical Safety]] INCHEM |access-date=9 June 2009 | editor = Ruse M}}
* {{cite journal | vauthors = Longo LP, Johnson B | title = Addiction: Part I. Benzodiazepines—side effects, abuse risk and alternatives | journal = [[American Family Physician]] | volume = 61 | issue = 7 | pages = 2121–2128 | date = April 2000 | pmid = 10779253 | url = https://www.aafp.org/pubs/afp/issues/2000/0401/p2121.html | access-date = 25 May 2008 | archive-date = 12 May 2008 | archive-url = https://web.archive.org/web/20080512180747/http://www.aafp.org/afp/20000401/2121.html | url-status = live }}

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